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Physicians can significantly impact both the quality and the cost of health care. Thus, it is not surprising that there is great interest in modifying physician behavior. There have been three main methods used to alter physician behavior: education, motivation, and facilitation. This article reviews the success of these methods. [ABSTRACT FROM AUTHOR]

Rates of Blount disease and childhood obesity have increased in parallel, although the co-management of this acquired comorbidity and obesity is not well described. This report shares the course of a toddler with severe obesity who experienced rapid and persistent weight gain without success from nutrition and behavior changes. After repeat subspeciality evaluation, the patient was ultimately diagnosed with signs of early-onset Blount disease, urging the need for adjunct medical therapy. Initiation of topiramate was shown to achieve weight neutrality and improve the patient's body mass index (BMI), appearing to halt the progression of Blount disease and avoiding escalation to surgical treatment. This report suggests topiramate can be an effective and well-tolerated medication in young patients with a pressing need for weight intervention., (© 2024 The Authors.)

Introduction: Bedside cardiac assessment (BCA) is deficient across a spectrum of noncardiology trainees. Learners not taught BCA well may become instructors who do not teach well, creating a self-perpetuating problem. To improve BCA teaching and learning, we developed a high-quality, patient-centered curriculum for medicine clerkship students that could be flexibly implemented and accessible to other health professions learners., Methods: With a constructivist perspective, we aligned learning goals, activities, and assessments. The curriculum used a "listen before you auscultate" framework, capturing patient history as context for a six-step, systematic approach. In the flipped classroom, short videos and practice questions preceded two 1-hour class activities that integrated diagnostic reasoning, pathophysiology, physical diagnosis, and reflection. Activities included case discussions, jugular venous pressure evaluation, heart sound competitions, and simulated conversations with patients. Two hundred sixty-eight students at four US and international medical schools participated. We incorporated feedback, performed thematic analysis, and assessed learners' confidence and knowledge., Results: Low posttest data capture limited quantitative results. Students reported increased confidence in BCA ability. Knowledge increased in both BCA and control groups. Thematic analysis suggested instructional design strategies were effective and peer encounters, skills practice, and encounters with educators were meaningful., Discussion: The curriculum supported active learning of day-to-day clinical competencies and promoted professional identity formation alongside BCA ability. Feedback and increased confidence on the late-clerkship posttest suggested durable learning. We recommend approaches to confirm this and other elements of knowledge, skill acquisition, or behaviors and are surveying impacts on professional identity formation-related constructs., (© 2023 Meisel et al.)

Background: Long-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) was approved by the U.S. Food and Drug Administration in December 2021. This initial phase of implementation represents a prime opportunity to ensure equitable LAI-PrEP provision to communities often underrepresented in PrEP care before disparities in access and uptake emerge. Herein, we describe the EquiPrEP Project which utilizes an equity-oriented implementation science framework to optimize LAI-PrEP rollout in an urban safety-net clinic in New York City., Methods: The primary objectives of this project are to: (1) increase LAI-PrEP initiation overall; (2) increase uptake among groups disproportionately impacted by the HIV epidemic; (3) preserve high PrEP retention while expanding use; and (4) identify barriers and facilitators to LAI-PrEP use. EquiPrEP will enroll 210 PrEP-eligible participants into LAI-PrEP care with planned follow-up for one year. We will recruit from the following priority populations: Black and/or Latine men who have sex with men, Black and/or Latine cisgender women, and transgender women and nonbinary individuals. To evaluate implementation of LAI-PrEP, we will utilize equity-focused iterations of the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework and the Consolidated Framework for Implementation Research (CFIR), in addition to longitudinal surveys and qualitative interviews., Discussion: Novel LAI-PrEP formulations carry tremendous potential to revolutionize the field of HIV prevention. Implementation strategies rooted in equity are needed to ensure that marginalized populations have access to LAI-PrEP and to address the structural factors that hinder initiation and retention in care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kaul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the spring of 2022, mpox spread to non-endemic countries, including the United States. In New York City (NYC), vaccine demand grew as quickly as case counts. With the leadership of the Regional Emerging Special Pathogens Treatment Center (RESPTC) at NYC Health and Hospitals/Bellevue (NYC H+H)-part of the largest public hospital system in the United States-an innovative vaccination model was established that overcame challenges involving health inequities, inadequate access, and lack of vaccine uptake, to successfully administer JYNNEOS vaccines to over 12,000 patients. Transmission has slowed since its peak in August 2022, which has been attributed to successful vaccination campaigns, infection-induced immunity, and behavioral changes among those at highest risk; however, a Centers for Disease Control and Prevention (CDC) assessment released on 4 April 2023 suggests jurisdictions with low vaccination levels (<35%) remain at risk for an mpox resurgence. Here, we summarize the critical aspects of our mpox vaccination model in NYC, which include integration into routine clinical care, prioritization of health equity, and reutilization of COVID-19 vaccination systems, to provide valuable insights for healthcare institutions as we move into the next stage of this ongoing outbreak.

The coronavirus disease 2019 (COVID-19) pandemic has caused more than 675 million confirmed cases and nearly 7 million deaths worldwide [1]. While testing for COVID-19 was initially centered in health care facilities, with required reporting to health departments, it is increasingly being performed in the home with rapid antigen testing [2]. Most at-home tests are self-interpreted and not reported to a provider or health department, which could lead to delayed reporting or underreporting of cases [3]. As such, there is a strong possibility that reported cases may become a less reliable indicator of transmission over time., Competing Interests: Potential conflicts of interest. All authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Similar to the early phases of the COVID-19 pandemic, New York City was the national epicenter of the ongoing 2022 mpox (formerly monkeypox) outbreak. Cases quickly began to rise in July 2022, primarily in gay, bisexual, or other men who have sex with men. Tools in the form of a reliable diagnostic test, an effective vaccine, and a viable treatment option have been available from the onset, although logistically complex to roll out. The special pathogens program at NYC Health + Hospitals/Bellevue, the flagship facility for the largest public hospital system in the United States, collaborated with multiple departments within Bellevue, the hospital system, and the NYC Department of Health and Mental Hygiene, to swiftly establish ambulatory testing, immunizations, patient-centered inpatient care, and outpatient therapeutics. With the ongoing mpox outbreak, hospitals and local health departments must prepare a systemwide response to identify and isolate patients and provide high-quality care. Findings from our experience can help guide institutions in developing a multipronged, comprehensive response to the ongoing mpox outbreak.

The recruitment of DRP1 to mitochondrial membranes prior to fission is facilitated by the wrapping of endoplasmic reticulum (ER) membranes around the mitochondria. To investigate the complex interplay between the ER membranes and DRP1 in the context of mitochondrial structure and function, we downregulate two key ER shaping proteins, RTN4 and CLIMP-63, and demonstrate pronounced mitochondrial hyperfusion and reduced ER-mitochondria contacts, despite their differential regulation of ER architecture. Although mitochondrial recruitment of DRP1 is unaltered in cells lacking RTN4 or CLIMP-63, several aspects of mitochondrial function, such as mtDNA-encoded translation, respiratory capacity and apoptosis are significantly hampered. Further mechanistic studies reveal that CLIMP-63 is required for cristae remodeling (OPA1 proteolysis) and DRP1-mediated mitochondrial fission, whereas both RTN4 and CLIMP-63 regulate the recruitment of BAX to ER and mitochondrial membranes to enable cytochrome c release and apoptosis, thereby performing novel and distinct roles in the regulation of mitochondrial structure and function., (© 2022. The Author(s).)

Reports conflict on how HIV infection influences the clinical course of COVID-19. The New York City (NYC) public hospital system provides care for over 14,000 people with HIV, was central in responding to the COVID-19 pandemic, and is therefore in a unique position to evaluate the intersection of these concurrent infections. Retrospective chart review of patients presenting to NYC Health and Hospitals (NYC H+H) diagnosed with COVID-19 infection from March 1, 2020, through April 28, 2020, compared people living with HIV (PLWH) and a propensity-matched (PM) control group of patients without HIV to evaluate associations between HIV status and COVID-19 outcomes. Two hundred thirty-four PLWH presented for COVID-19 testing and 110 (47%) were diagnosed with COVID-19. Among 17,413 patients with COVID-19 and without HIV, 1:n nearest neighbor propensity score matching identified 194 patients matched on age, sex, race, and any comorbidity. In the sample with COVID-19 ( N  = 304), PLWH (9.1%) had lower rates of mortality than controls [19.1%; PM odds ratio (PM-OR): 0.41, 95% confidence interval (CI): 0.19-0.86]. Among hospitalized COVID-19 patients ( N  = 179), HIV infection was associated with lower rates of mechanical ventilation (PM-OR: 0.31, 95% CI: 0.11-0.84) and mortality (PM-OR: 0.40, 95% CI: 0. 17-0.95). In the extended pandemic period through April 2021, aggregate data by HIV status suggested elevated hospitalization and mortality rates in PLWH versus people without HIV. These results suggest that the direct biological impacts of the HIV virus do not negatively influence COVID-19-related outcomes when controlling for comorbidity and demographic variables.

Objectives: To evaluate the impact of ICU surge on mortality and to explore clinical and sociodemographic predictors of mortality., Design: Retrospective cohort analysis., Setting: NYC Health + Hospitals ICUs., Patients: Adult ICU patients with coronavirus disease 2019 admitted between March 24, and May 12, 2020., Interventions: None., Measurements and Main Results: Hospitals reported surge levels daily. Uni- and multivariable analyses were conducted to assess factors impacting in-hospital mortality. Mortality in Hispanic patients was higher for high/very high surge compared with low/medium surge (69.6% vs 56.4%; p = 0.0011). Patients 65 years old and older had similar mortality across surge levels. Mortality decreased from high/very high surge to low/medium surge in, patients 18-44 years old and 45-64 (18-44 yr: 46.4% vs 27.3%; p = 0.0017 and 45-64 yr: 64.9% vs 53.2%; p = 0.002), and for medium, high, and very high poverty neighborhoods (medium: 69.5% vs 60.7%; p = 0.019 and high: 71.2% vs 59.7%; p = 0.0078 and very high: 66.6% vs 50.7%; p = 0.0003). In the multivariable model high surge (high/very high vs low/medium odds ratio, 1.4; 95% CI, 1.2-1.8), race/ethnicity (Black vs White odds ratio, 1.5; 95% CI, 1.1-2.0 and Asian vs White odds ratio 1.5; 95% CI, 1.0-2.3; other vs White odds ratio 1.5, 95% CI, 1.0-2.3), age (45-64 vs 18-44 odds ratio, 2.0; 95% CI, 1.6-2.5 and 65-74 vs 18-44 odds ratio, 5.1; 95% CI, 3.3-8.0 and 75+ vs 18-44 odds ratio, 6.8; 95% CI, 4.7-10.1), payer type (uninsured vs commercial/other odds ratio, 1.7; 95% CI, 1.2-2.3; medicaid vs commercial/other odds ratio, 1.3; 95% CI, 1.1-1.5), neighborhood poverty (medium vs low odds ratio 1.6, 95% CI, 1.0-2.4 and high vs low odds ratio, 1.8; 95% CI, 1.3-2.5), comorbidities (diabetes odds ratio, 1.6; 95% CI, 1.2-2.0 and asthma odds ratio, 1.4; 95% CI, 1.1-1.8 and heart disease odds ratio, 2.5; 95% CI, 2.0-3.3), and interventions (mechanical ventilation odds ratio, 8.8; 95% CI, 6.1-12.9 and dialysis odds ratio, 3.0; 95% CI, 1.9-4.7) were significant predictors for mortality., Conclusions: Patients admitted to ICUs with higher surge scores were at greater risk of death. Impact of surge levels on mortality varied across sociodemographic groups., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Although 2/3 of US adults and nearly 1/3 of US children have overweight or obesity, weight stigma is common. Many with overweight or obesity ascribe negative ideas to themselves, resulting in internalized weight bias (IWB). In adults, IWB has been associated with psychosocial problems; however, this relationship has been studied little in children. This study aims to describe IWB in children with overweight and obesity and to study the association of children's IWB with experienced weight bias, self-esteem, and their parents' IWB. Methods: Children ages 9-18 with overweight or obesity completed the Weight Bias Internalization Scale (WBIS), Rosenberg Self-Esteem Scale, and Perception of Teasing Scale; parents completed the Weight Bias Internalization Scale-Modified and the Perceived Weight Discrimination Scale. Descriptive statistics were used to assess IWB, self-esteem, and experienced weight stigma. Chi-square and t -tests were used to examine associations between categorical and continuous variables, respectively. Multivariate linear regression was used to identify correlates of IWB in children. Results: Of 111 child participants, the median WBIS score was 2.8 out of 7. Higher IWB was associated with more peer teasing ( p  < 0.001) and lower self-esteem ( p  < 0.001). IWB in children was not associated with child BMI z-score ( p  = 0.590) or higher parent IWB ( p  = 0.287). Conclusions: Children with overweight and obesity who have experienced more teasing by peers or who have lower self-esteem are more likely to have a higher IWB. However, increasing child BMI z-score and parent IWB are not associated with higher child IWB.

Background: Despite evidence of socio-demographic disparities in outcomes of COVID-19, little is known about characteristics and clinical outcomes of patients admitted to public hospitals during the COVID-19 outbreak., Objective: To assess demographics, comorbid conditions, and clinical factors associated with critical illness and mortality among patients diagnosed with COVID-19 at a public hospital in New York City (NYC) during the first month of the COVID-19 outbreak., Design: Retrospective chart review of patients diagnosed with COVID-19 admitted to NYC Health + Hospitals / Bellevue Hospital from March 9th to April 8th, 2020., Results: A total of 337 patients were diagnosed with COVID-19 during the study period. Primary analyses were conducted among those requiring supplemental oxygen (n = 270); half of these patients (135) were admitted to the intensive care unit (ICU). A majority were male (67.4%) and the median age was 58 years. Approximately one-third (32.6%) of hypoxic patients managed outside the ICU required non-rebreather or non-invasive ventilation. Requirement of renal replacement therapy occurred in 42.3% of ICU patients without baseline end-stage renal disease. Overall, 30-day mortality among hypoxic patients was 28.9% (53.3% in the ICU, 4.4% outside the ICU). In adjusted analyses, risk factors associated with mortality included dementia (adjusted risk ratio (aRR) 2.11 95%CI 1.50-2.96), age 65 or older (aRR 1.97, 95%CI 1.31-2.95), obesity (aRR 1.37, 95%CI 1.07-1.74), and male sex (aRR 1.32, 95%CI 1.04-1.70)., Conclusion: COVID-19 demonstrated severe morbidity and mortality in critically ill patients. Modifications in care delivery outside the ICU allowed the hospital to effectively care for a surge of critically ill and severely hypoxic patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Family-oriented therapies are the gold standard of childhood obesity treatment, yet little is known about if or how information gathered by one parent from a health care provider is translated to the home. We assessed how families of children and adolescents with overweight and obesity communicate weight-related information received from their provider to family members not present at the visit. Methods: Parents and children (9-18 years old, N  = 112) completed the McMaster's Family Assessment Device Communication Subscale (FADc) and investigator-derived questions describing weight-related communication practices with family members. We used descriptive statistics to describe communication practices and separate logistic regression models to assess associations of communication practices with parent-reported FADc, child BMI z -score, child sex, parent BMI, household income, and site. Results: Most parents discuss with other family members: their child's weight (60.4%) or weight management discussions with the child's provider (57.9%). Median parent FADc score was 2.0 (IQR 0.5). The most common facilitator to weight-related conversations was understanding what the provider said (95.1%). Higher FADc score (worse communication) was associated with whether parents ask other family members' opinions about weight information received from their child's provider [odds ratio 0.22 (95% confidence interval 0.05-0.99)]. Higher income was associated with many healthy communication practices. Conclusions: Slightly more than half of parents discuss with family members what their provider said regarding their child's weight. More effort must be placed on aiding parents in relaying information from the provider to other family members in the home to encourage family lifestyle changes and alleviate childhood obesity.

Objective: The primary aim of this study was to determine the association of an integrated mental health training model on pediatric residents' use of (1) secondary screens, (2) mental health referrals, (3) psychotropic medications, and (4) follow-up appointments for mental health concerns. The secondary aim was to determine resident confidence managing mental health conditions., Methods: Visits of children ages 6-18 years old with either a positive primary mental health screen or a mental health diagnosis in pre- and post-intervention years (N = 113 and N = 251, respectively) at a single-site continuity clinic were included. Authors also surveyed alumni from pre- and post- intervention years (N = 46) about their confidence with managing mental health disorders. The authors used chi-squared and t-tests to compare visit characteristics between years and multivariable logistic regression to determine correlates of mental health management., Results: Post-intervention residents more often used secondary screening tools (adjusted odds ratio 5.61, 95% confidence interval 2.08-15.17). There were no differences in referrals, prescribing psychotropic medications, or follow-up visits. Post-intervention graduates reported higher confidence with diagnosis, screening, medication management, and follow-up for mental health disorders., Conclusions: After transitioning to an integrated mental health model, residents were more likely to use secondary screens and post-intervention graduates reported higher confidence with managing mental health disorders.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-X L , and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-X L and MCL-1, with little or no BCL-2. Although expression levels of BCL-X L and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-X L and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.

Maintenance of mitochondrial integrity is critical for normal cellular homoeostasis. Most cells respond to stress stimuli and undergo apoptosis by perturbing mitochondrial structure and function to release proteins, such as cytochrome c , which are essential for the execution of the intrinsic apoptotic cascade. Cancer cells evade these events by overexpressing the anti-apoptotic BCL-2 family of proteins on mitochondrial membranes. Inhibitors of the anti-apoptotic BCL-2 family proteins, also known as BH3 mimetics, antagonise the pro-survival functions of these proteins and result in rapid apoptosis. Although the precise mechanism by which BH3 mimetics induce apoptosis has been well characterised, not much is known in terms of the structural changes that occur in mitochondria during apoptosis. Using a panel of highly selective BH3 mimetics and a wide range of cell lines, we demonstrate that BH3 mimetics induce extensive mitochondrial fission, accompanied by swelling of the mitochondrial matrix and rupture of the outer mitochondrial membrane. These changes occur in a BAX/ BAK-dependent manner. Although a major mitochondrial fission GTPase, DRP-1, has been implicated in mitochondrial apoptosis, our data demonstrate that DRP-1 might function independently/downstream of BH3 mimetic-mediated mitochondrial fission to facilitate the release of cytochrome c and apoptosis. Moreover, downregulation of DRP-1 prevented cytochrome c release and apoptosis even when OPA1, a protein mediating mitochondrial fusion, was silenced. Although BH3 mimetic-mediated displacement of BAK and other BH3-only proteins from BCL-X L and MCL-1 was unaffected by DRP-1 downregulation, it prevented BAK activation significantly, thus placing DRP-1 as one of the most critical players, along with BAX and BAK, that governs BH3 mimetic-mediated cytochrome c release and apoptosis., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

The endoplasmic reticulum (ER) with its elaborate network of highly curved tubules and flat sheets interacts with several other organelles, including mitochondria, peroxisomes and endosomes, to play vital roles in their membrane dynamics and functions. Previously, we identified structurally diverse chemicals from different pharmacological classes, which induce a reversible reorganisation of ER membranes. Using apogossypol as a prototypic tool compound, we now show that ER membrane reorganisation occurs at the level of ER tubules but does not involve ER sheets. Reorganisation of ER membranes prevents DRP-1-mediated mitochondrial fission, thereby antagonising the functions of several mitochondrial fission-inducing agents. Previous reports have suggested that ER membranes mark the constriction sites of mitochondria by localising DRP-1, as well as BAX on mitochondrial membranes to facilitate both mitochondrial fission and outer membrane permeabilisation. Following ER membrane reorganisation and subsequent exposure to an apoptotic stimulus (BH3 mimetics), DRP-1 still colocalises with the reorganised ER membranes but BAX translocation and activation, cytochrome c release and phosphatidylserine externalisation are all inhibited, thereby diminishing the ability of BH3 mimetics to induce the intrinsic apoptotic pathway. Strikingly, both ER membrane reorganisation and its resulting inhibition of apoptosis could be reversed by inhibitors of dihydroorotate dehydrogenase (DHODH), namely teriflunomide and its active metabolite, leflunomide. However, neither genetic inhibition of DHODH using RNA interference nor metabolic supplementation with orotate or uridine to circumvent the consequences of a loss of DHODH activity rescued the effects of DHODH inhibitors, suggesting that the effects of these inhibitors in preventing ER membrane reorganisation is most likely independent of their ability to antagonise DHODH activity. Our results strengthen the hypothesis that ER is fundamental for key mitochondrial functions, such as fusion-fission dynamics and apoptosis.

The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines. Furthermore, S63845 synergizes with other BH3 mimetics to induce apoptosis in cell lines derived from both hematological and solid tumors. Although the anti-apoptotic BCL-2 family members in these cell lines interact with a spectrum of pro-apoptotic BH3-only proteins to regulate apoptosis, these interactions alone do not explain the relative sensitivities of these cell lines to BH3 mimetic-induced apoptosis. These findings necessitated further investigation into the requirement of BH3-only proteins in BH3 mimetic-mediated apoptosis. Concurrent inhibition of BCL-X L and MCL-1 by BH3 mimetics in colorectal HCT116 cells induced apoptosis in a BAX- but not BAK-dependent manner. Remarkably this apoptosis was independent of all known BH3-only proteins. Although BH3-only proteins were required for apoptosis induced as a result of BCL-X L inhibition, this requirement was overcome when both BCL-X L and MCL-1 were inhibited, implicating distinct mechanisms by which different anti-apoptotic BCL-2 family members may regulate apoptosis in cancer.

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-X L (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy., (Copyright© 2019 Ferrata Storti Foundation.)

Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure. These shared effects on mitochondrial morphology indicate a similar function of these anti-apoptotic BCL-2 proteins in maintaining mitochondrial integrity and function.

Human herpesvirus-8 (HHV-8) remains best known as an oncogenic virus, but nonneoplastic disease manifestations, such as bone marrow failure or hemophagocytic lymphohistiocytosis (HLH) have gained greater recognition in recent years. In organ transplantation, HHV-8 infection commonly occurs with reactivation of latent virus among recipients from endemic regions of the world or due to transmission from the organ donor. We describe a case of HHV-8-associated HLH in a liver transplant recipient at increased risk for primary infection. Our case highlights the risk of non-donor-derived, posttransplant primary HHV-8 infection, and demonstrates that HLH can be a life-threatening complication of this infection.

[This corrects the article DOI: 10.1155/2017/5474916.].

Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo , S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein., Competing Interests: CONFLICTS OF INTEREST P Casara and JA Hickman are former employees of Institut de Recherches Servier. M Chanrion, A Claperon, F Colland, O Geneste, AM Girard, F Gravé, G Guasconi, JM Henlin, G Le Toumelin-Braizat, G Lysiak-Auvity, F Rocchetti, E Schneider, JB Starck and A Studeny are full-time employees of Institut de Recherches Servier. T Le Diguarher is a full-time employee of Technology Servier. A Bruno and L Kraus-Berthier are full-time employees of Institut de Recherches Internationales Servier. E Morris, S Qiu and Y Wang are full-time employees of Novartis Institutes for BioMedical Research; E Morris and Y Wang are stock owner of Novartis. S LeGouill has served on advisory board for Servier. Amiot and Cohen's laboratories have received research funds from Servier. I Chen, J Davidson, P Dokurno, C Graham, N Matassova, J Murray, C Pedder, N Whitehead, M Wood are full-time employees of Vernalis Ltd. R Hubbard is a part-time employee of Vernalis Ltd.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context. To address the lack of standardised assays for benchmarking the in vitro binding of putative inhibitors before analysis of their cellular effects, we developed a rapid differential scanning fluorimetry (DSF)-based assay, and used it to screen a panel of BH3 mimetics. We next contrasted their binding signatures with their ability to induce apoptosis in a MCL-1 dependent cell line. Of all the MCL-1 inhibitors tested, only A-1210477 induced rapid, concentration-dependent apoptosis, which strongly correlated with a thermal protective effect on MCL-1 in the DSF assay. In cells that depend on both MCL-1 and BCL-X L , A-1210477 exhibited marked synergy with A-1331852, a BCL-X L specific inhibitor, to induce cell death. Despite this selectivity and potency, A-1210477 induced profound structural changes in the mitochondrial network in several cell lines that were not phenocopied following MCL-1 RNA interference or transcriptional repression, suggesting that A-1210477 induces mitochondrial fragmentation in an MCL-1-independent manner. However, A-1210477-induced mitochondrial fragmentation was dependent upon DRP-1, and silencing expression levels of DRP-1 diminished not just mitochondrial fragmentation but also BH3 mimetic-mediated apoptosis. These findings provide new insights into MCL-1 ligands, and the interplay between DRP-1 and the anti-apoptotic BCL-2 family members in the regulation of apoptosis.

Background: Picky eating and food neophobia are common during childhood. Childhood eating behaviors are often predictive of adult eating behaviors., Objectives: Determine if childhood picky eating or food neophobia is associated with childhood weight status, or with becoming underweight, overweight, or obese later in childhood., Data Sources: We identified relevant studies from searches of PubMed, PsycINFO, and NEOHAL, as well as citations from identified studies. Study Eligibility Criteria and Participants: Inclusion criteria were original research articles examining a relationship between picky eating and/or food neophobia with childhood weight status. We summarized definitions and prevalence of picky eating or food neophobia and association with weight status., Study Appraisal: Two independent investigators assessed bias and confounding using the Agency for Healthcare Research and Quality's RTI Item Bank., Results: Forty-one studies met inclusion criteria. Picky eating was defined inconsistently, and a large variation in prevalence was found (5.8%-59%). Food neophobia was consistently defined as an unwillingness to try new foods, with a prevalence between 40% and 60%. No association existed between childhood weight status and food neophobia, and results were unclear for picky eating., Limitations: Risk of bias and confounding were moderate. Parental report was commonly used to assess picky eating, height, and weight and parental weight, feeding styles, and community characteristics were infrequently considered., Conclusions and Implications: Heterogeneous definitions used for picky eating led to a wide range of reported prevalence and an unclear relationship with weight. Consistent definitions and an improved understanding of such a relationship could help clinicians provide appropriate anticipatory guidance.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a predictive biomarker of disease progression in many malignancies, including imatinib-treated chronic myeloid leukemia (CML). Although high CIP2A levels correlate with disease progression in CML, the underlying molecular mechanisms remain elusive. In a screen of diagnostic chronic phase samples from patients with high and low CIP2A protein levels, high CIP2A levels correlate with an antiapoptotic phenotype, characterized by downregulation of proapoptotic BCL-2 family members, including BIM, PUMA and HRK, and upregulation of the antiapoptotic protein BCL-XL. These results suggest that the poor prognosis of patients with high CIP2A levels is due to an antiapoptotic phenotype. Disrupting this antiapoptotic phenotype by inhibition of BCL-XL via RNA interference or A-1331852, a novel, potent and BCL-XL-selective inhibitor, resulted in extensive apoptosis either alone or in combination with imatinib, dasatinib or nilotinib, both in cell lines and in primary CD34(+) cells from patients with high levels of CIP2A. These results demonstrate that BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML.

Background: Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell-permeable, selective inhibitors of BCL-2, BCL-XL and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells., Methods: We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells., Results: Both BH3 profiling and the inhibitor toolkit effectively predict chemosensitivity of cells addicted to a single anti-apoptotic protein but a combination of both techniques is more instructive when cell survival depends on more than one anti-apoptotic protein., Conclusions: The inhibitor toolkit provides a rapid, inexpensive and simple means to assess the chemosensitivity of tumour cells and in conjunction with BH3 profiling offers much potential in personalising cancer therapy.

The overweight and obesity epidemic among children and adolescents in the United States continues to worsen, with notable racial, ethnic, and socioeconomic disparities. Risk factors for pediatric obesity include genetics; environmental and neighborhood factors; increased intake of sugar-sweetened beverages (SSBs), fast-food, and processed snacks; decreased physical activity; shorter sleep duration; and increased personal, prenatal, or family stress. Pediatricians can help prevent obesity by measuring body mass index at least yearly and providing age- and development-appropriate anticipatory guidance to families. Public policies and environmental interventions aim to make it easier for children to make healthy nutrition and physical activity choices. Interventions focused on family habits and parenting strategies have also been successful at preventing or treating childhood obesity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

The anti-apoptotic BCL-2 family proteins are important targets for cancer chemotherapy. Specific and potent inhibitors of the BCL-2 family, such as ABT-263 (navitoclax) and ABT-199, are only effective against some members of the BCL-2 family but do not target MCL-1, which is commonly amplified in tumors and associated with chemoresistance. In this report, the selectivity and potency of two putative MCL-1 inhibitors, dinaciclib and maritoclax, were assessed. Although both compounds induced Bax/Bak- and caspase-9-dependent apoptosis, dinaciclib was more potent than maritoclax in downregulating MCL-1 and also in inducing apoptosis. However, the compounds induced apoptosis, even in cells lacking MCL-1, suggesting multiple mechanisms of cell death. Furthermore, maritoclax induced extensive mitochondrial fragmentation, and a Bax/Bak- but MCL-1-independent accumulation of mitochondrial reactive oxygen species (ROS), with an accompanying loss of complexes I and III of the electron transport chain. ROS scavengers, such as MitoQ, could not salvage maritoclax-mediated effects on mitochondrial structure and function. Taken together, our data demonstrate that neither dinaciclib nor maritoclax exclusively target MCL-1. Although dinaciclib is clearly not a specific MCL-1 inhibitor, its ability to rapidly downregulate MCL-1 may be beneficial in many clinical settings, where it may reverse chemoresistance or sensitize to other chemotherapeutic agents.

Processing and synthesis of purified nanomaterials of diverse composition, size, and properties is an evolving process. Studies have demonstrated that some nanomaterials have potential toxic effects and have led to toxicity research focusing on nanotoxicology. About two million workers will be employed in the field of nanotechnology over the next 10 years. The unknown effects of nanomaterials create a need for research and development of techniques to identify possible toxicity. Through a cooperative effort between National Institute for Occupational Safety and Health and IBM to address possible occupational exposures, silicon-based nanowires (SiNWs) were obtained for our study. These SiNWs are anisotropic filamentary crystals of silicon, synthesized by the vapor-liquid-solid method and used in bio-sensors, gas sensors, and field effect transistors. Reactive oxygen species (ROS) can be generated when organisms are exposed to a material causing cellular responses, such as lipid peroxidation, H2O2 production, and DNA damage. SiNWs were assessed using three different in vitro environments (H2O2, RAW 264.7 cells, and rat alveolar macrophages) for ROS generation and possible toxicity identification. We used electron spin resonance, analysis of lipid peroxidation, measurement of H2O2 production, and the comet assay to assess generation of ROS from SiNW and define possible mechanisms. Our results demonstrate that SiNWs do not appear to be significant generators of free radicals.

Setting: We conducted a retrospective study among HIV-infected adult suspects (≥18 years) with pulmonary tuberculosis (TB), who underwent Xpert MTB/RIF (Xpert) testing at McCord Hospital and its adjoining HIV clinic in Durban, South Africa., Objective: To determine if Xpert testing performed at a centralized laboratory accelerated time to TB diagnosis., Design: We obtained data on sputum smear microscopy [acid-fast bacilli (AFB)], Xpert, and the rationale for treatment initiation from medical records. The primary outcome was "total diagnostic time," defined as time from sputum collection to clinicians' receipt of results. A linear mixed-effect model compared the duration of steps in the diagnostic pathway across testing modalities., Results: Among 403 participants, the median "total diagnostic time" for AFB and Xpert was 3.3 and 6.4 days, respectively (P < 0.001). When compared with AFB, the median delay for Xpert "laboratory processing" was 1.4 days (P < 0.001) and "result transfer to clinic" was 1.7 days (P < 0.001). Among 86 Xpert-positive participants who initiated treatment, 49 (57%) started treatment based on clinical suspicion or AFB-positive results, whereas only 32 (37%) started treatment based on Xpert-positive results., Conclusions: In our setting, Xpert results took twice as long as AFB results to reach clinicians. Replacing AFB with centralized Xpert may delay TB diagnoses in some settings.

This study evaluated how educational attainment impacts clinical outcomes of HIV-positive patients in Durban, South Africa. The authors conducted a prospective study of 466 adult HIV-positive patients initiating antiretroviral therapy (ART) at an urban TB-HIV clinic from October 2004 to June 2007. The level of educational attainment (highest grade completed) was assessed at ART initiation. The authors measured tuberculosis treatment outcomes as well as death, lost to follow-up, viral suppression (HIV RNA <400 copies/mL), and immunologic response (CD4 ≥200 cells/mm(3)) at 6, 12, and 24 months after ART initiation. After 24 months of ART initiation, there were 43 deaths; viral suppression and immunologic response were observed in 88% and 83% of the remaining patients, respectively. The authors found no association between level of educational attainment and mortality (P = .12), loss to follow-up (P = .85), virologic response (P = .51), or immunologic response (P = .63). Similar findings were observed at 6 and 12 months post-ART initiation., (© The Author(s) 2013.)

High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-XL but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak- and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2- or BCL-XL-dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

BAK activation represents a key step during apoptosis, but how it converts into a mitochondria-permeabilizing pore remains unclear. By further delineating the structural rearrangements involved, we reveal that BAK activation progresses through a series of independent steps: BH3-domain exposure, N-terminal change, oligomerization, and membrane insertion. Employing a "BCL-XL-addiction" model, we show that neutralization of BCL-XL by the BH3 mimetic ABT-737 resulted in death only when cells were reconstituted with BCL-XL:BAK, but not BCL-2/ BCL-XL:BIM complexes. Although this resembles the indirect model, release of BAK from BCL-XL did not result in spontaneous adoption of the pore conformation. Commitment to apoptosis required association of the direct activator BIM with oligomeric BAK promoting its conversion to a membrane-inserted pore. The sequential nature of this cascade provides multiple opportunities for other BCL-2 proteins to interfere with or promote BAK activation and unites aspects of the indirect and direct activation models., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)