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Objective: Acute promyelocytic leukemia (APL) is associated with an elevated risk of developing disseminated intravascular coagulation (DIC). The purpose of this study was to assess the outcomes of hospitalizations related to DIC in APL and their impact on healthcare., Materials and Methods: This study entailed a cross-sectional and retrospective analysis of the US National Inpatient Sample database. We identified adults with APL and categorized them into groups of patients with and without DIC. Our focus areas included in-hospital mortality, length of stay, charges, and complications associated with DIC. Unadjusted odds ratios/coefficients were computed in univariate analysis, followed by adjusted odds ratios (aOR)/coefficients from multivariate analysis that accounted for confounding factors., Results: Our analysis revealed that APL patients with DIC had a substantially higher aOR for mortality (aOR: 6.68, 95% confidence interval [CI]: 4.76-9.37, p<0.001) and a prolonged length of stay (coefficient: 10.28 days, 95% CI: 8.48-12.09, p<0.001) accompanied by notably elevated total hospital charges (coefficient: $215,512 [95% CI: 177,368-253,656], p<0.001), thereby emphasizing the reality of extended medical care and economic burden. The presence of DIC was associated with increased odds of sepsis, vasopressor support, pneumonia, acute respiratory failure, intubation/mechanical ventilation, and acute kidney injury, reflecting heightened vulnerability to these complications. Patients with DIC demonstrated significantly higher odds ratios for major bleeding, intracranial hemorrhage, gastrointestinal bleeding, red blood cell transfusion, platelet transfusion, fresh frozen plasma transfusion, and cryoprecipitate transfusion, highlighting the pronounced hematological risks posed by DIC., Conclusion: This study has revealed the significant associations between DIC in APL and various outcomes, underscoring the clinical and economic implications of these conditions. The hematological risks further increase patients’ vulnerability to bleeding events and the need for transfusions., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2024 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House.)

Diabetes technology has undergone a remarkable evolution in the past decade, with dramatic improvements in accuracy and ease of use. Continuous glucose monitor (CGM) technology, in particular, has evolved, and coevolved with widely available consumer smartphone technology, to provide a unique opportunity to both improve management and decrease the burden of management for populations across nearly the entire spectrum of people living with diabetes. Capitalizing on that opportunity, however, will require both adoption of and adaptations to the use of CGM technology in the broader world of primary care. This article focuses on mechanisms to expand pathways to optimized glycemic management, thereby creating a robust roadway capable of improving care across broad populations managed in primary care settings. Recent expansions in access to devices combined with improved mechanisms for data access at the time of primary care visits and improved training and evolving systems of support within primary care, hold potential to improve glycemic management in diabetes across the health care spectrum., Competing Interests: T.W.M. is employed by HealthPartners Institute, which has contracts with Abbott Diabetes Care, Dexcom, Eli Lilly, Insulet, Medscape, Medtronic, Novo Nordisk, Sanofi US Services, Inc., and Tandem for his services as a research investigator, speaker, and/or consultant. He is paid on salary and receives no personal income from any of these services. No other potential conflicts of interest relevant to this article were reported., (© 2023 by the American Diabetes Association.)

Importance: Surgical resection remains the preferred treatment for functionally fit patients diagnosed with early-stage non-small cell lung cancer (NSCLC). Process-based intraoperative quality metrics (QMs) are important for optimizing long-term outcomes following curative-intent resection., Objective: To develop a practical surgical quality score for patients diagnosed with clinical stage I NSCLC who received definitive surgical treatment., Design, Setting, and Participants: This retrospective cohort study used a uniquely compiled data set of US veterans diagnosed with clinical stage I NSCLC who received definitive surgical treatment from October 2006 through September 2016. The data were analyzed from April 1 to September 1, 2022. Based on contemporary treatment guidelines, 5 surgical QMs were defined: timely surgery, minimally invasive approach, anatomic resection, adequate lymph node sampling, and negative surgical margin. The study developed a surgical quality score reflecting the association between these QMs and overall survival (OS), which was further validated in a cohort of patients using data from the National Cancer Database (NCDB). The study also examined the association between the surgical quality score and recurrence-free survival (RFS)., Exposures: Surgical treatment of early-stage NSCLC., Main Outcomes and Measures: Overall survival and RFS., Results: The study included 9628 veterans who underwent surgical treatment between 2006 and 2016. The cohort consisted of 1446 patients who had a mean (SD) age of 67.6 (7.9) years and included 9278 males (96.4%) and 350 females (3.6%). Among the cohort, 5627 individuals (58.4%) identified as being smokers at the time of surgical treatment. The QMs were met as follows: timely surgery (6633 [68.9%]), minimally invasive approach (3986 [41.4%]), lobectomy (6843 [71.1%]) or segmentectomy (532 [5.5%]), adequate lymph node sampling (3278 [34.0%]), and negative surgical margin (9312 [96.7%]). The median (IQR) follow-up time was 6.2 (2.5-11.4) years. An integer-based score (termed the Veterans Affairs Lung Cancer Operative quality [VALCAN-O] score) from 0 (no QMs met) to 13 (all QMs met) was constructed, with higher scores reflecting progressively better risk-adjusted OS. The median (IQR) OS differed substantially between the score categories (score of 0-5 points, 2.6 [1.0-5.7] years of OS; 6-8 points, 4.3 [1.7-8.6] years; 9-11 points, 6.3 [2.6-11.4] years; and 12-13 points, 7.0 [3.0-12.5] years; P < .001). In addition, risk-adjusted RFS improved in a stepwise manner between the score categories (6-8 vs 0-5 points, multivariable-adjusted hazard ratio [aHR], 0.62; 95% CI, 0.48-0.79; P < .001; 12-13 vs 0-5 points, aHR, 0.39; 95% CI, 0.31-0.49; P < .001). In the validation cohort, which included 107 674 nonveteran patients, the score remained associated with OS., Conclusions and Relevance: The findings of this study suggest that adherence to intraoperative QMs may be associated with improved OS and RFS. Efforts to improve adherence to surgical QMs may improve patient outcomes following curative-intent resection of early-stage lung cancer.

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

The chloride intracellular channel (CLIC) protein family displays the unique feature of altering its structure from a soluble form to a membrane-bound chloride channel. CLIC1, a member of this family, is found in the cytoplasm or in internal and plasma membranes, with membrane relocalisation linked to endothelial disfunction, tumour proliferation and metastasis. The molecular switch promoting CLIC1 activation remains under investigation. Here, cellular Cl- efflux assays and immunofluorescence microscopy studies have identified intracellular Zn2+ release as the trigger for CLIC1 activation and membrane insertion. Biophysical assays confirmed specific binding to Zn2+, inducing membrane association and enhancing Cl- efflux in a pH-dependent manner. Together, our results identify a two-step mechanism with Zn2+ binding as the molecular switch promoting CLIC1 membrane insertion, followed by pH-mediated activation of Cl- efflux., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Older adults continue to drink as they age. Aging changes alcohol kinetics just as with any other drug. Older adults have increased sensitivity to acute alcohol intake that accounts for the increased risk of falls, traffic accidents, and other injury. The Annual Medicare Wellness Exam is an excellent opportunity to introduce screening for unsafe drinking along with accumulated risks and deficits of aging. Older adults have responded well to brief interventions for unhealthy drinking. In the presence of alcohol use disorder or serious comorbidity including psychiatric illness, referral to specialized multidisciplinary care can be lifesaving., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spontaneous coronary artery dissection is a rare condition that can precipitate acute coronary syndrome in pregnant and peripartum women. A 32-year-old previously healthy female, 2-weeks post-partum, presented to the emergency department after sudden cardiac arrest. Return of spontaneous circulation was achieved after multiple rounds of resuscitation. Electrocardiogram revealed ST elevations in the anterolateral leads with reciprocal changes. She was taken to the catheterization lab by cardiology and was found to have a dissection of the distal left anterior descending coronary artery. The patient was subsequently treated medically with heparin and antiplatelet therapy, but ultimately died of anoxic encephalopathy. The purpose of this report is to describe the risk factors, presentation, and management of spontaneous coronary artery dissection which can be easily overlooked given its rarity., Topics: Spontaneous coronary artery dissection, out-of-hospital cardiac arrest, peri-partum complications., (© 2021 Kim, et al.)

Melanomas only account for 4% of all dermatologic cancers yet are responsible for 80% of deaths. Notably, melanomas of the hand and foot have a worse prognosis when compared with melanomas of other anatomic regions. Likely this is due to intrinsic biologic characteristics, delayed diagnosis, difficult surgical excision due to delicate anatomy, and lack of definitive diagnostic and therapeutic guidelines. The most common locations of melanoma of the hand, in order of decreasing frequency, are subungual area, dorsal surface, and palmar surface. The most common locations of melanoma of the foot are the plantar surface, dorsal surface, and subungual area, in decreasing frequency. Diagnosis of melanoma of the hand and foot can be difficult because the traditional "ABCDE" (asymmetric shape, border, color, diameter, evolution) rules do not apply. Newer acronyms have been proposed in literature including "CUBED" (colored, uncertain, bleeding, enlarged, delayed) and "ABC rule for Subungual Melanoma." Once diagnosed, treatment is primarily surgical excision and reconstruction. The goal for the surgeon is to maintain the function and anatomy of the hand or foot., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In the midst of competing priorities and limited resources in low-middle-income countries (LMIC), convincing epidemiological evidence is critical for urging governments to develop national dementia plans. The majority of primary epidemiological studies on dementia are from high income countries (HIC). Implications for developing countries are typically extrapolated from these outcomes through modeling, meta-analyses, and systematic reviews. In this study, we directly assessed the incidence of dementia, disability adjusted life years (DALYs), and cost of care among community-dwelling Filipino elderly. Methods: This was a follow-up study of the prospective cohort Marikina Memory Ageing Project (MMAP). Baseline assessment was performed in 2011-2012, and follow-up was done in 2015-2016 ( N = 748 at follow-up). Incident dementia was determined. Disease burden was computed using the incidence rates and DALYs. Both indirect and direct (medical and non-medical) costs of dementia care were computed. Results: The crude incidence rate was 16 (CI: 13-20) cases per 1,000 person-years (pyr) with 17 (CI: 12-21) per 1,000 pyr for females and 14 (CI: 9-21) per 1,000 pyr for males. Based on this incidence, we project an estimation of 220,632 new cases in 2030, 295,066 in 2040, and 378,461 in 2050. Disease burden was at 2,876 DALYsper 100,000 persons. The economic burden per patient was around Php 196,000 annually (i.e., ~4,070 USD, or 36.7% of average family annual income in the Philippines). The majority (86.29%) of this care expense was indirect cost attributed to estimated lost potential earning of unpaid family caregivers whereas direct medical cost accounted for only 13.48%. Conclusions: We provide the first Filipino community-based data on the incidence of dementia, DALYs, and cost of care to reflect the epidemiologic and economic impact of disease. The findings of this study serve to guide the development of a national dementia plan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dominguez, Jiloca, Fowler, De Guzman, Dominguez-Awao, Natividad, Domingo, Dominguez, Reandelar, Ligsay, Yu, Aichele and Phung.)

Interventions on graft bifurcation lesions are uncommon, especially in the setting of acute coronary syndromes (ACS). We described three cases of graft bifurcation intervention where we tailored our approach based on lesion characteristics, anatomy, and angulation to achieve excellent angiographic and clinical outcomes. In case 1, shared ostia of saphenous vein graft (SVG) to Diagonal (D) and Radial graft to Obtuse Marginal (OM) was severely stenosed. We prioritized the radial arterial graft as it is known to have a longer patency rate over a totally occluded SVG of an undetermined period. We performed provisional stenting of the ostium of the radial artery and balloon angioplasty of the SVG ostium, while stenting the body of the SVG. In case 2 (bifurcation lesion at the anastomosis of SVG to D1 and sequential jump graft to OM), we utilized a V stenting strategy after an embolization protection device (EPD) was deployed in the branch with a suitable landing zone. Kissing balloon dilatation of both the branches was performed both pre- and poststenting. In case 3 (bifurcation lesion at SVG to OM and Sequential "T" graft to diagonal), there was >90% angulation between both the grafts. We used "T" stenting strategy in this case. At 2-year follow-up, patients had no major adverse cardiovascular events since and remained symptom free., (© 2021 Wiley Periodicals LLC.)

In patients with septic shock, hydrocortisone 200-400 mg/d has been shown to reverse shock compared with placebo. Lower doses of hydrocortisone have not previously been studied, and there are no previous studies comparing two different doses of hydrocortisone. At our institution, some clinicians routinely prescribe doses less than 200 mg/d. This study aims to compare the effect of lower doses of hydrocortisone to standard doses on shock reversal and adverse events in septic shock., Design: Retrospective cohort study., Setting: Single-center medical ICU., Subjects: Patients who received hydrocortisone for septic shock., Interventions: Electronic chart review., Measurements and Main Results: Patients were divided into low-dose hydrocortisone (75-150 mg/d) and standard-dose hydrocortisone (200-400 mg/d) cohorts based on initial prescribed hydrocortisone dose. Rates of shock reversal and adverse events in the two cohorts were compared. Two-hundred thirteen patients were included-41 in low-dose and 172 in standard-dose cohorts. Baseline characteristics including initial vasopressor requirement and Sequential Organ Failure Assessment scores were similar. Average rates of change in vasopressor needs, conditional hazard rate for vasopressor withdrawal, and cumulative probability for vasopressor withdrawal were all quantitatively similar for low-dose and standard-dose hydrocortisone. Insulin requirement (particularly in those with diabetes mellitus), blood glucose in those with diabetes mellitus, and frequency of secondary infections seemed to be lower in the low-dose hydrocortisone cohort. Mortality and other secondary outcomes were similar., Conclusions: In septic shock, hydrocortisone dosed 75-150 mg/d appears to reverse shock as effectively 200-400 mg/d and may cause a lower frequency of adverse events., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Vitamin D deficiency has become an increasing focus of clinical interest, especially in understanding its associations with obesity in adults. The pathological associations linking the two appear to demonstrate complex cellular inflammatory, hormonal and genetic pathways. Enhanced understanding at both microcellular and clinical levels will help clarify the role of obesity in the development of vitamin D deficiency.

Introduction: All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults., Materials and Methods: Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation., Results: The value of the combined genetic + clinical multiple moderator (M cg ) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (M c ) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism., Discussion: These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach., (Copyright © 2019. Published by Elsevier Ltd.)

Anthracyclines are an effective chemotherapy agent. However, very few cases of idarubicin-induced cardiomyopathy exist. Herein, we describe a case of first-dose idarubicin-related acute heart failure in a woman with a history of myelodysplastic syndrome converted to acute myeloid leukaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Distal renal tubular acidosis is a relatively infrequent condition with complex pathophysiology that can present with life-threatening electrolyte abnormalities., Case Presentation: We describe a case of a 57-year-old Caucasian woman with previous episodes of hypokalemia, severe muscle weakness, and fatigue. Upon further questioning, symptoms of dry eye and dry mouth became evident. Initial evaluation revealed hyperchloremic metabolic acidosis, severe hypokalemia, persistent alkaline urine, and a positive urinary anion gap, suggestive of distal renal tubular acidosis. Additional laboratory workup and renal biopsy led to the diagnosis of primary Sjögren's syndrome with associated acute tubulointerstitial nephritis. After potassium and bicarbonate supplementation, immunomodulatory therapy with hydroxychloroquine, azathioprine, and prednisone was started. Nonetheless, her renal function failed to improve and remained steady with an estimated glomerular filtration rate of 42 ml/min/1.73 m 2 . The literature on this topic was reviewed., Conclusions: Cases of renal tubular acidosis should be carefully evaluated to prevent adverse complications, uncover a potentially treatable condition, and prevent the progression to chronic kidney disease. Repeated episodes of unexplained hypokalemia could be an important clue for diagnosis.

The management of coronary thrombus is not well defined. Current therapies include medical management with anticoagulation, antiplatelet, and thrombolytic therapies or revascularization with percutaneous coronary interventions including mechanical thrombectomy, and coronary artery bypass grafting surgery. In this report, we present a patient with significant left main coronary artery thrombus burden with advanced cirrhosis and recent esophageal variceal bleeding who was successfully treated with conservative medical management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

It is unknown whether patients with LTBI at high vs. low risk of developing active TB are currently adequately identified and treated in the US. In this study our objective was 1) To retrospectively apply the online calculator (tstin3d.com) to determine the probability of having LTBI and assign cumulative risk of progression. 2) Measure treatment outcomes in subjects with Low: 0-<10%, Intermediate: 10-<50% and High: 50-100% cumulative risk. We performed medical record review of tuberculin skin test and/or Interferon-γ release assay (IGRAs) positive patients with LTBI seen from 2010-2015. Of 125 subjects included, 51(41%), 46 (37%) and 28 (22%) subjects were in Low, Intermediate and High risk groups respectively. Tstin3d.com was useful in determining the probability of LTBI in tuberculin skin test positive US-born subjects. Overall treatment completion rate was 61% in 114 subjects with complete treatment information and similar completion rates were seen in the three groups (Low-60%, Intermediate-63% and High-57%). Provider assessment of important clinical risk factors was often incomplete. Logistic regression analysis showed no association of assessment of important risk factors with treatment completion. The major limitations of the calculator are the lack of an updated data on country-specific prevalence of TB disease as the global burden of TB continues to decrease as well as falsely high positive predictive values that due to "transiently" positive IGRA results in subjects from countries with low prevalence. Nonetheless, our findings suggest that tstin3d.com could be utilized in the US setting for improving providing awareness of risk stratification of patients with LTBI for short course treatment regimens based on risk., Competing Interests: The authors have declared that no competing interests exist.

Background Atrial fibrillation ( AF ) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF . Methods and Results We conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF . There have also been non-ion channel mutations that have been linked to AF . Genome-wide association studies have helped in identifying potential links between single-nucleotide polymorphisms and AF . Ancestry studies have also highlighted a role of genetics in AF . Blacks with a higher percentage of European ancestry are at higher risk of developing AF . The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation. Conclusions The evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.

Background: Cancer survivors face psychosocial issues that increase their risk of suicide. This study examined the risk of suicide across cancer sites, with a focus on survivors of head and neck cancer (HNC)., Methods: The Surveillance, Epidemiology, and End Results 18-registry database (from 2000 to 2014) was queried for the top 20 cancer sites in the database, including HNC. The outcome of interest was suicide as a cause of death. The mortality rate from suicide was estimated for HNC sites and was compared with rates for 19 other cancer sites that were included in the study. Poisson regression was used to estimate adjusted rate ratios (aRRs) and 95% confidence intervals (CIs) for 1) HNC versus non-HNC sites (the other 19 cancer sites combined), and 2) HNC versus each individual cancer site. Models were stratified by sex, controlling for race, marital status, age, year, and stage at diagnosis., Results: There were 404 suicides among 151,167 HNC survivors from 2000 to 2014, yielding a suicide rate of 63.4 suicides per 100,000 person-years. In this timeframe, there were 4493 suicides observed among 4219,097 cancer survivors in the study sample, yielding an incidence rate of 23.6 suicides per 100,000 person-years. Compared with survivors of other cancers, survivors of HNC were almost 2 times more likely to die from suicide (aRR, 1.97; 95% CI, 1.77-2.19). There was a 27% increase in the risk of suicide among HNC survivors during the period from 2010 to 2014 (aRR, 1.27; 95% CI, 1.16-1.38) compared with the period from 2000 to 2004., Conclusions: Although survival rates in cancer have improved because of improved treatments, the risk of death by suicide remains a problem for cancer survivors, particularly those with HNC., (© 2018 American Cancer Society.)

Theory: In the Project on the Good Physician, the authors propose a moral intuitionist model of virtuous caring that places the virtues of Mindfulness, Empathic Compassion, and Generosity at the heart of medical character education., Hypotheses: Hypothesis 1a: The virtues of Mindfulness, Empathic Compassion, and Generosity will be positively associated with one another (convergent validity). Hypothesis 1b: The virtues of Mindfulness and Empathic Compassion will explain variance in the action-related virtue of Generosity beyond that predicted by Big Five personality traits alone (discriminant validity). Hypothesis 1c: Virtuous students will experience greater well-being ("flourishing"), as measured by four indices of well-being: life meaning, life satisfaction, vocational identity, and vocational calling (predictive validity). Hypothesis 1d: Students who self-report higher levels of the virtues will be nominated by their peers for the Gold Humanism Award (predictive validity). Hypothesis 2a-2c: Neuroticism and Burnout will be positively associated with each other and inversely associated with measures of virtue and well-being., Method: The authors used data from a 2011 nationally representative sample of U.S. medical students (n = 499) in which medical virtues (Mindfulness, Empathic Compassion, and Generosity) were measured using scales adapted from existing instruments with validity evidence., Results: Supporting the predictive validity of the model, virtuous students were recognized by their peers to be exemplary doctors, and they were more likely to have higher ratings on measures of student well-being. Supporting the discriminant validity of the model, virtues predicted prosocial behavior (Generosity) more than personality traits alone, and students higher in the virtue of Mindfulness were less likely to be high in Neuroticism and Burnout., Conclusions: Data from this descriptive-correlational study offered additional support for the validity of the moral intuitionist model of virtuous caring. Applied to medical character education, medical school programs should consider designing educational experiences that intentionally emphasize the cultivation of virtue.

In susceptible tumor cells, DNA-damaging antineoplastic agents induce an increase in intracellular pH during the premitochondrial stage of apoptosis. The rate of nonenzymatic deamidation of two asparagines in the anti-apoptotic protein Bcl-x L is accelerated by this increase in pH. Deamidation of these asparagines is a signal for the degradation of Bcl-x L , which is a component of the apoptotic response to DNA damage. It has previously been shown that the increase in pH is mediated by the ion transporter Na + /H + exchanger 1 in some cells. Here we demonstrate that one or more additional ion transporters also have a role in the regulation of Bcl-x L deamidation in at least some tumor cell lines and fibroblasts. As a second, independent finding, we report that there are histidines in close proximity to the Bcl-x L deamidation sites that are highly conserved in land-dwelling species and we present evidence that deamidation of human Bcl-x L is intramolecularly catalyzed in a manner that is dependent upon these histidines. Further, we present evidence that these histidines act as a pH-sensitive switch that enhances the effect of the increase in pH on the rate of Bcl-x L deamidation. The conservation of such histidines implies that human Bcl-x L is in essence "designed" to be deamidated, which provides further evidence that deamidation serves as a bona fide regulatory post-translational modification of Bcl-x L ., (Copyright © 2018 Elsevier B.V. All rights reserved.)

SIRT7, a member of the sirtuin family, with coenzyme NAD catalyzes protein deacetylation and has been implicated in multiple biologic processes; however, its function in mammalian oocytes remains to be explored. Here, we report disrupted meiotic maturation upon specific knockdown of SIRT7 in mouse oocytes. In particular, disorganized spindle/chromosomes and the loss of the cortical actin cap are readily observed in SIRT7-depleted oocytes, generating aneuploid eggs. Furthermore, we found that SIRT7 depletion markedly elevated reactive oxygen species levels in oocytes, thereby compromising the developmental competence of early embryos. Of note, SIRT7 protein level is significantly decreased in oocytes from obese mice, and the forced expression of exogenous SIRT7 ameliorates maternal obesity-associated meiotic defects and oxidative stress in oocytes. In summary, our data suggest that SIRT7 is an essential factor in the determination of oocyte quality and may mediate the effects of obesity on female reproduction.-Gao, M., Li, X., He, Y., Han, L., Qiu, D., Ling, L., Liu, H., Liu, J., Gu, L. SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation.

Dendritic cells (DCs) are an indispensable part of studying human responses that are important for protective immunity against cancer and infectious diseases as well as prevention of autoimmunity and transplant rejection. These cells are also key elements of personalized vaccines for cancer and infectious diseases. Despite the vital role of DCs in both clinical and basic research contexts, methods for obtaining these cells from individuals remains a comparatively under-developed and inefficient process. DCs are present in very low concentrations (<1%) in blood, thus they must be generated from monocytes and the current methodology in DC generation involves a laborious process of static culture and stimulation with cytokines contained in culture medium. Herein, we describe an automated fluidic system, MicroDEN, that allows for differentiation of monocytes into immature-DCs (iDCs) utilizing continuous perfusion of differentiation media. Manual steps associated with current ex vivo monocyte differentiation are vastly reduced and an aseptic environment is ensured by the use of an enclosed cartridge and tubing network. Benchmark phenotyping was performed on the generated iDCs along with allogeneic T-cell proliferation and syngeneic antigen-specific functional assays. MicroDEN generated iDCs were phenotypically and functionally similar to well plate generated iDCs, thereby demonstrating the feasibility of utilizing MicroDEN in the broad range of applications requiring DCs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m 2 (given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m 2 and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer.

Objectives: Current international guidelines for ocular radiation exposure suggest a threshold of 20 millisieverts (mSv)/year. Although endoscopists wear lead aprons, use of protective eye wear is optional. This study was conducted to analyze the lens radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) for endoscopists to determine the time of fluoroscopy needed to warrant using lens protection during ERCP., Methods: ERCP patients were prospectively enrolled. Indications, interventions, fluoroscopy time, dose, and attending ± fellow involvement were recorded. Radiation exposure was collected from body dosimeters and dosimeters placed between the eyes. Cumulative radiation doses were obtained at study completion and averaged over the total fluoroscopy time to determine the mSv/hour exposure., Results: A total of 187 cases were included. Attendings and fellows wore lens dosimeters in 178 and 126 cases, respectively, and body dosimeters in 174 and 128 cases, respectively. Attendings and fellows wore lens dosimeters throughout 15.89 and 11.24 h of fluoroscopy, respectively. The cumulative radiation dose absorbed per lens dosimeters was 5.35 mSv for attendings and 2.55 mSv for fellows. The projected lens absorption by the body dosimeters was 19.03 mSv for attendings and 5.21 mSv for fellows. The hourly fluoroscopy lens exposure was 0.34 mSv/hour for attendings and 0.23 mSv/hour for fellows., Conclusions: The amount of fluoroscopy hours needed to reach the currently suggested lens threshold limit (20 mSv/year) was 59.41 h for attendings and 88.17 h for fellows. Radioprotective eye wear should be worn by physicians with yearly fluoroscopy times in similarly structured practices that meet or exceed these thresholds.

Background: Research on inpatient palliative medicine reports quality-of-life outcomes and selected "hard" outcomes including pain scores, survival, and readmissions., Objective: This case study reports the evolution of an inpatient palliative consultation (IPC) team to show how IPC induces culture change in a hospital that previously had no palliative care., Design: Retrospective chart review., Setting: A Catholic university-affiliated, inner-city hospital., Population: A total of 1700 consecutive adult inpatients from May 2009 to October 2013., Measures: Consultation records enumerated demographics, code status, powers of attorney, referring physician, reason for consultation, and discharge destination. Deidentified data were uploaded to a spreadsheet. Simple descriptive statistics were calculated., Results: Requests originated from internal medicine (24%), geriatrics (21%), neurology (including stroke and neurosurgery, 14.3%), medical intensive care unit (MICU, 12.2%), and hematology-oncology (10.3%). The MICU consults increased 17.6% over time. The numbers of consults nearly doubled after trainees began rounding with the service. Hospice discharges increased by 9.2%. Palliative management of in-hospital expirations increased 2- to 3-fold. The most common consultation requests were for pain and nonpain symptoms, establishing goals of care for patients experiencing clinical decline and convening family meetings in cases of divided judgment., Conclusion: We describe the evolution of palliative care in a safety-net hospital. Medicine services which are largely resident run adopted early. Specialty services that are attending driven adopted later. We believe house staff and nurses were the initial change agents. The number of consultations increased when house staff and students began rotating on the service suggesting unmet demand due to the limited supply of providers.

Background: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2)., Patients and Methods: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin R Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM SM ) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015., Results: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2., Conclusions: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The chloride intracellular channel (CLIC) 5A is expressed at very high levels in renal glomeruli, in both endothelial cells (EC) and podocytes. CLIC5A stimulates Rac1- and phosphatidylinositol (4,5)-bisphosphate-dependent ERM (ezrin, radixin, moesin) activation. ERM proteins, in turn, function in lumen formation and in the development of actin-based cellular projections. In mice lacking CLIC5A, ERM phosphorylation is profoundly reduced in podocytes, but preserved in glomerular EC. Since glomerular EC also express CLIC4, we reasoned that, if CLIC4 activates ERM proteins like CLIC5A, then CLIC4 could compensate for the CLIC5A loss in glomerular EC. In glomeruli of CLIC5-deficient mice, CLIC4 expression was upregulated and colocalized with moesin and ezrin in glomerular EC, but not in podocytes. In cultured glomerular EC, CLIC4 silencing reduced ERM phosphorylation and cytoskeletal association, and expression of exogenous CLIC4 or CLIC5A rescued ERM de-phosphorylation due to CLIC4 silencing. In mice lacking either CLIC4 or CLIC5, ERM phosphorylation was retained in glomerular EC, but, in mice lacking both CLIC4 and CLIC5, glomerular EC ERM phosphorylation was profoundly reduced. Although glomerular EC fenestrae developed normally in dual CLIC4/CLIC5-deficient mice, the density of fenestrae declined substantially by 8 mo of age, along with the deposition of subendothelial electron-lucent material. The dual CLIC4/CLIC5-deficient mice developed spontaneous proteinuria, glomerular cell proliferation, and matrix deposition. Thus CLIC4 stimulates ERM activation and can compensate for CLIC5A in glomerular EC. The findings indicate that CLIC4/CLIC5A-mediated ERM activation is required for maintenance of the glomerular capillary architecture., (Copyright © 2016 the American Physiological Society.)

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.

Purpose: Arm exercise is an alternative to pharmacologic stress testing for >50% of patients unable to perform treadmill exercise, but no data exist regarding the effect of attained peak arm exercise heart rate on test sensitivity. Thus, the purpose of this investigation was to characterize the relationship of peak arm exercise heart rate responses to abnormal stress test findings, coronary revascularization, and mortality in patients unable to perform leg exercise., Methods: From 1997 until 2002, arm cycle ergometer stress tests were performed in 443 consecutive veterans age 64.1 yr (11.0 yr) (mean (SD)), of whom 253 also underwent myocardial perfusion imaging (MPI). Patients were categorized by frequency distributions of quartiles of percentage age-predicted peak heart rate (APPHR), heart rate reserve (HRR), and peak heart rate-systolic blood pressure product (PRPP). Exercise-induced ST-segment depression, abnormal MPI findings, coronary revascularization, and 12.0-yr (1.3 yr) Kaplan-Meier all-cause and cardiovascular mortality plots were then characterized by quartiles of APPHR, HRR, and PRPP., Results: A reduced frequency of abnormal arm exercise ECG results was associated only with the lowest quartile of APPHR (≤69%) and HRR (≤43%), whereas higher frequency of abnormal MPI findings exhibited an inverse relationship trend with lower APPHR (P = 0.10) and HRR (P = 0.12). There was a strong inverse association of APPHR, HRR, and PRPP with all-cause (all P ≤ 0.01) and cardiovascular (P < 0.05) mortality. The frequency of coronary revascularization was unrelated to APPHR or HRR., Conclusions: Arm exercise ECG stress test sensitivity is only reduced at ≤69% APPHR or ≤43% HRR, whereas arm exercise MPI sensitivity and referral for coronary revascularization after arm exercise stress testing are not adversely affected by even a severely blunted peak heart rate. However, both all-cause mortality and cardiovascular mortality are strongly and inversely related to APPHR and HRR.

Background: Effective use of the convex curvilinear ultrasound bronchoscope in the esophagus (EUS-B) for fine needle aspiration biopsy of mediastinal structures is now well described. In contrast, there is little to no reporting, depending on the site of EUS-B for access to sub-diaphragmatic structures. Our practice has been accessing sub-diaphragmatic sites for years. This review documents our experience with EUS-B to biopsy liver, left adrenal glands, and coeliac lymph nodes., Methods: After Institutional Review Board's approval, all endosonographic procedures performed by interventional pulmonary between July 2013 and June 2015 were reviewed. Those including biopsy of sub-diaphragmatic sites were then selected for analysis., Results: Over the study interval, 45 sub-diaphragmatic biopsy procedures (25 left adrenal glands, 7 liver, and 13 celiac node) were performed with EUS-B. In all cases, cellular adequacy was present, and samples were large enough for immunohistochemistry and any relevant ancillary studies. Metastatic malignancy was documented in 58% of cases, 16% of cases contained benign diagnostic findings, and in 27% of cases, normal organ tissue was documented. There were no complications., Conclusions: Operators comfortable with the endobronchial ultrasound scope in both the airway and the esophagus can actively seek and successfully perform biopsy of sub-diaphragmatic abnormalities when present and can thereby add to the diagnostic value of the procedure.