Trapped fat: Obesity pathogenesis as an intrinsic disorder in metabolic fuel partitioning.

Our understanding of the pathophysiology of obesity remains at best incomplete despite a century of research. During this time, two alternative perspectives have helped shape thinking about the etiology of the disorder. The currently prevailing view holds that excessive fat accumulation results because energy intake exceeds energy expenditure, with excessive food consumption being the primary cause of the imbalance. The other perspective attributes the initiating cause of obesity to intrinsic metabolic defects that shift fuel partitioning from pathways for mobilization and oxidation to those for synthesis and storage. The resulting reduction in fuel oxidation and trapping of energy in adipose tissue drives a compensatory increase in energy intake and, under some conditions, a decrease in expenditure. This theory of obesity pathogenesis has historically garnered relatively less attention despite its pedigree. Here, we present an updated comprehensive formulation of the fuel partitioning theory, focused on evidence gathered over the last 80 years from major animal models of obesity showing a redirection of fuel fluxes from oxidation to storage and accumulation of excess body fat with energy intake equal to or even less than that of lean animals. The aim is to inform current discussions about the etiology of obesity and by so doing, help lay new foundations for the design of more efficacious approaches to obesity research, treatment and prevention.

Rationale for Hepatitis C Virus Treatment During Hematopoietic Stem Cell Transplant in the Era of Novel Direct-Acting Antivirals.

BACKGROUND AND AIMS: Untreated hepatitis C (HCV) infection in patients undergoing hematopoietic stem cell transplantation (HSCT) can lead to worse outcomes. Traditionally, HSCT patients infected with HCV would wait until after immune reconstitution to receive HCV therapy, as the oncologic urgency of transplant would not allow time for a full preceding treatment course of HCV therapy. However, in the era of newer direct-acting antivirals (DAAs), we propose that concomitant treatment of HCV while undergoing HSCT is safe and feasible, while keeping in mind potential drug-drug interactions. METHODS: A literature review was performed to summarize the available data on the impact of HCV on patients undergoing HSCT. Drug-drug interactions for DAA's and pertinent HSCT drugs were evaluated using Lexicomp online® and http://hep-druginteractions.org . RESULTS: During HSCT, HCV appears to be a conditional risk factor for sinusoidal obstruction syndrome and a potential risk factor for graft versus host disease, both of which are associated with increased mortality. HCV reactivation and exacerbation may impact the use of chemotherapeutics, but available studies haven't shown impact specifically on HSCT. Limited case reports exist but demonstrate safe and effective use DAAs during HSCT. These, along with a drug-drug interaction review demonstrate agents such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are promising DAAs for use in HSCT. CONCLUSION: HCV infection may worsen outcomes for patients undergoing HSCT. Concomitant treatment of HCV during HSCT using newer DAAs appears feasible and may improve patient morbidity and mortality, however large-scale studies are needed to further support this practice.

Impact of Patient Blood Management on Red Blood Cell Utilization in an Urban Community Teaching Hospital: A Seven-Year Retrospective Study.

OBJECTIVES: This study aimed to showcase how implementing a patient blood management (PBM) program effectively cuts unnecessary red blood cell (RBC) transfusions in a New York City urban community teaching hospital. METHODS: Analyzing seven years from 2013 to 2019, a retrospective review of RBC transfusions was conducted. RESULTS: Following the introduction of PBM, considerable improvements were observed annually. These included a drop in mean pretransfusion hemoglobin levels from 7.26 g/dL (2013) to 6.58 g/dL (2019), a 34% reduction in yearly RBC unit transfusions, and fewer units given to patients with pre-Hgb levels ≥ 7 g/dL (from 1210 units in 2013 to 310 units in 2019). Furthermore, this study noted a decline in two-unit RBC orders when Hgb levels were ≥ 7 g/dL from 65 orders in 2013 to merely 3 in 2019. The estimated total cost savings attributed to the six-year PBM program duration after full implementation in 2014 amounted to USD 2.1 million. CONCLUSIONS: Overall, PBM implementation significantly decreased RBC transfusions and enhanced transfusion practices. The findings emphasize that successful PBM strategies do not always necessitate extensive resources or increased budgets but instead rely on the application of intuitive methods, as evidenced by this study.

Determination of Unnecessary Blood Transfusion by Comprehensive 15-Hospital Record Review.

BACKGROUND: Although unnecessary blood component transfusions are costly and pose substantial patient risks, the extent of unnecessary blood use in a community hospital setting has not been systematically measured. METHODS: A 15-hospital observational analysis was performed using comprehensive retrospective review. Approximately 100 encounters (x¯â€¯= 103.9, standard deviation [SD] ± 7.6) per hospital (6,696 total component transfusion events) were reviewed between 2012 and 2018. Review was performed by two medical directors. Findings were supported by blind intra- and inter-reviewer double review and blind external review by 10 independent reviewers. RESULTS: Patients received an average of 4.3 (± 1.3) units. Only 8.2% (± 6.7) of patient encounters did not receive unnecessary units. Fifty-five percent (54.6% ± 13.5) could have been managed without at least one component type, while 44.6% (± 14.9) could have been managed completely without transfusion. Forty-five percent (45.4% ± 17.0) of red blood cell, 54.9% (± 19.3) of plasma-cryoprecipitate, and 38.0% (± 15.6) of plateletpheresis encounters could likely have been managed without transfusion. Between 2,713 units (40.5%) and 3,306 units (49.4%) were likely unnecessary. In patients who could have been managed without transfusion of at least one component type, unnecessary blood use was associated with a 0.38 (± 0.11)-day increase in length of hospital stay for each additional unnecessary unit received (p < 0.001). CONCLUSION: Substantial unnecessary blood use was identified, all of which was unrecognized by hospitals prior to review. Unnecessary blood use was attributed to overreliance on laboratory transfusion criteria and failure to follow common blood management principles, which resulted in potential harm to patients and avoidable cost.

Critical conversations on patient blood management with clinical colleagues.

Although a subspecialty-trained transfusion medicine (TM) physician brings value to the clinical bedside, hospital transfusion service oversight often falls under the responsibility of pathologists primarily focused on surgical pathology. Yet, pathologists who lack TM fellowship training may not be quite as confident in their role as the TM physician in-charge, especially when the need to communicate with another clinician arises. Given that blood is a resource subject to frequent shortages, there is a need for constant monitoring of blood utilization such that those responsible for transfusion service oversight need to handle challenging clinical interactions when transfusion guidelines are breeched. Generally, the average pathologist is more knowledgeable regarding blood component therapy than other clinician. Yet, disagreements concerning patient transfusion management can arise, in spite of established evidence-based hospital transfusion guidelines. Since authoritative fact stating is not likely to be effective in changing the entrenched practices, pathologists must engage in strategies that will develop meaningful working relationships with their clinical colleagues. Such strategies include being a visible part of direct patient care, such as attendance at patient rounds or provision of mini-consultations by phone regarding transfusion management. Inviting clinicians to attend the hospital transfusion committee meetings and scheduling educational grand rounds are also useful strategies. Clinicians may be more receptive to blood conservation during times of shortages if open communication is established, particularly if hospital leadership is involved in urgent crisis messaging to the clinicians and other hospital staff involved in patient care.

Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.

Malignant colon polyps: predicting lymph node metastasis following endoscopic excision.

AIM: The risk of lymph node metastasis (LNM) of malignant colon polyps (MCPs) is partly estimated by histologic features of the sampled polyp. However, the routinely available histologic data is limited to tumor grade and status of lymphovascular invasion (LVI). METHODS: The NCDB for colon cancer 2004-2018 was utilized. Patients with pT1Nx adenocarcinoma arising in a polyp and undergoing partial colectomy with ≥ 12 retrieved nodes were selected. NCDB 2004-2017 was used as a training cohort to develop two scoring systems based on a multivariable regression for predictors of LNM including clinical characteristics, grade, and LVI: a nomogram scoring system (NSS) and a simplified scoring system (SSS). These models were internally validated using NCDB 2018 to calculate precision metrics for each model. RESULTS: Six thousand sixty-nine patients were selected in the training cohort. 64.5% of MCPs were in the sigmoid, and LNM rate was 11.2%. Multivariable regression identified younger age, females, hindgut location, higher grade, and LVI as significant predictors of LNM. LNM risk was 1.2% when all unfavorable predictors were absent and exceeded 10% when NSS > 70 or SSS ≥ 3. In the 2018 validation cohort, 723 patients were scored per NSS and SSS, and the negative predictive value for both was 96%. CONCLUSION: Estimating LNM risk in MCPs by applying clinical characteristics along with limited histologic data can help inform decision-making when considering formal oncologic resection. The NSS and SSS demonstrated comparable predictability of LNM among pT1Nx MCPs. The models require external validation and may be strengthened by incorporating additional endoscopic and pathologic characteristics.

"Words Aren't Supposed to Hurt, But They Do": Sexual and Gender Minority Youth's Bullying Experiences.

Sexual and gender minority youth (SGMY) are more likely to experience bullying and violence compared to the youth who do not identify as SGMY, leading to increased risk of poor mental and physical health outcomes, and poor academic performance. Few studies explore the entire range of bullying experienced by sexual and gender minority youth (SGMY). The purpose of this study was to qualitatively describe the ways in which SGMY experience bullying victimization. We conducted semi-structured interviews with a diverse sample of 20 SGMY aged 14-18 years (median age 16 years) recruited from online social media. The sample included 10 participants who identified as cisgender girls, 4 who identified as cisgender boys, 2 who identified as transgender, and 4 who identified as another gender identity. Ten participants identified as bisexual, six identified as lesbian, and four identified as gay. Findings indicated six common experiences of bullying among the participants: (a) verbal harassment; (b) gender policing; (c) physical violence; (d) sexual harassment; (e) treated as sexual perpetrators and deviants; and (f) and social exclusion. SGMY described how bullying victimization ranged from overt to concealed attitudes and behaviors, and they articulated how several forms of bullying are likely not experienced by heterosexual and cisgender youth. These results support findings from prior qualitative studies and suggest that efforts to address school-based bullying may benefit from a more complete awareness of the range of bullying victimization experienced by SGMY. Development of multi-item scales of bullying that reflect the six common experiences of bullying presented in this study would allow researchers to quantitatively explore the range of bullying behaviors experienced by SGMY, and would aid in the conceptualization and successful implementation of anti-bullying interventions.

Using the Electronic Health Record to Characterize the Hepatitis C Virus Care Cascade.

OBJECTIVES: Chronic hepatitis C virus (HCV) infection is one of the main causes of hepatocellular carcinoma. Before initiating a multilevel HCV screening intervention, we sought to (1) describe concordance between the electronic health record (EHR) data warehouse and manual medical record review in recording aspects of HCV testing and treatment and (2) estimate the percentage of patients with chronic HCV infection who initiated and completed HCV treatment using manual medical record review. METHODS: We examined the medical records for 177 patients (100 randomly selected patients born during 1945-1965 without evidence of HCV testing and 77 adult patients of any birth cohort who had completed HCV testing) with a primary care or relevant specialist visit at an academic health care system in Tampa, Florida, from 2015 through 2018. We used the Cohen κ coefficient to examine the degree of concordance between the searchable data warehouse and the medical record review abstractions. Descriptive statistics characterized referral to and receipt of treatment among patients with chronic HCV infection from medical record review. RESULTS: We found generally good concordance between the data warehouse abstraction and medical record review for HCV testing data (κ ranged from 0.66 to 0.87). However, the data warehouse failed to capture data on HCV treatment variables. According to medical record review, 28 patients had chronic HCV infection; 16 patients were prescribed treatment, 14 initiated treatment, and 9 achieved and had a reported posttreatment undetected HCV viral load. CONCLUSIONS: Using data warehouse data provides generally reliable HCV testing information. However, without the use of natural language processing and purposeful EHR design, manual medical record reviews will likely be required to characterize treatment initiation and completion.

Histologic Diagnosis of Inflammatory Bowel Diseases.

Inflammatory bowel disease, including ulcerative colitis and Crohn disease, is an idiopathic chronic inflammatory condition of the gastrointestinal tract. Since neither the clinical manifestations nor the morphologic features of inflammatory bowel disease are pathognomonic alone, the differential diagnosis to consider is relatively broad, and it relies on the synthesis of clinical, endoscopic, and microscopic features. Long-held histologic diagnostic principles include recognizing structural and inflammatory features of chronicity, that is, architectural distortion, basal plasmacytosis, and expansion of the lamina propria lymphoplasmacytic infiltrate. In addition, evaluation of the neutrophilic inflammation and related crypt and epithelial destruction is essential to gauge the activity of the disease. Nevertheless, these features can be difficult to confirm in special settings, including at the inception of the disease or in partially treated cases. This review will explore the classic morphologic features of ulcerative colitis and Crohn disease, followed by a detailed discussion of atypical and diagnostically challenging presentations and a brief review of the clinical aspects necessary for the daily practice of pathologists.

Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis.

Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.

The carbohydrate-insulin model: a physiological perspective on the obesity pandemic.

According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body-resulting from the hormonal responses to a high-glycemic-load diet-drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.

Feasibility of a Web-Accessible Game-Based Intervention Aimed at Improving Help Seeking and Coping Among Sexual and Gender Minority Youth: Results From a Randomized Controlled Trial.

PURPOSE: To address the gap in interventions for improving sexual and gender minority youth (SGMY; e.g., lesbian, gay, bisexual, and transgender youth) health, we tested the feasibility of a game-based intervention for increasing help-seeking, productive coping skills, resource knowledge/use, and well-being. METHODS: We conducted a 2-arm randomized controlled trial testing a theory-based, community-informed, Web-accessible computer role-playing game intervention. Control condition received a list of resources. Primary hypotheses were high levels of implementation success, game demand, and game acceptability. RESULTS: We randomized 240 SGMYs aged 14-18 years into the intervention (n = 120) or control (n = 120) conditions. Participants completed baseline (100%), 1-month follow-up (T2; 73.3%), and 2-month follow-up (T3; 64.4%) surveys. Among intervention participants, 55.8% downloaded and played the game. Of those who played, 46.2% reported a desire to play it again, and 50.8% would recommend it. Game acceptability exceeded hypothesized benchmarks, wherein participants reported high positive affect (M = 2.36; 95% confidence interval [CI]: 2.13, 2.58), low negative affect (M = 2.75; 95% CI: 2.55, 2.95), low tension/annoyance (M = 3.18; 95% CI: 2.98, 3.39), and high competence (M = 2.23; 95% CI: 2.04, 2.43) while playing the game. In multivariable intent-to-treat analyses of 38 secondary/tertiary outcomes, intervention participants reported significantly larger reductions than control participants in cyberbullying victimization (T2 b = -.28; 95% CI: -.56, -.01), binge drinking frequency (T2 b = -.39; 95% CI: -.71, -.06), and marijuana use frequency (T3 b = -2.78; 95% CI: -4.49, -1.08). CONCLUSIONS: We successfully implemented a Web-accessible game trial with SGMY. The game-based intervention was feasible and acceptable to SGMY, and preliminary results show it improved several health-related behaviors. A larger scale trial is needed to test whether the game-based intervention can reduce health inequities for SGMY.

Transfusion-Associated Circulatory Overload and Transfusion-Related Acute Lung Injury.

OBJECTIVES: To review the new current diagnostic criteria of transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) from the literature while highlighting distinguishing features. We provide comprehensive understanding of the importance of hemovigilance and its role in appropriately identifying and reporting these potentially fatal transfusion reactions. METHODS: A review of the English language literature was performed to analyze TACO and TRALI while providing further understanding of the rationale behind the historical underrecognition and underreporting. RESULTS: Our review demonstrates the new 2018 and 2019 case definitions for TACO and TRALI, respectively. With more comprehensive diagnostic strategies, adverse transfusion events can be better recognized from mimicking events and underlying disease. In addition, there are mitigation strategies in place to help prevent complications of blood product transfusion, with emphasis on the prevention of TACO and TRALI. CONCLUSIONS: TACO and TRALI are potentially fatal adverse complications of blood transfusion. Both have been historically underrecognized and underreported due to poor defining criteria and overlapping symptomatology. Developing a thorough clinical understanding between these two entities can improve hemovigilance reporting and can contribute to risk factor identification and preventative measures.