Expression Ratios of the Antiapoptotic BCL2 Family Members Dictate the Selective Addiction of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Primary Effusion Lymphoma Cell Lines to MCL1.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several malignancies in people living with HIV, including primary effusion lymphoma (PEL). PEL cell lines exhibit oncogene addictions to both viral and cellular genes. Using CRISPR screens, we previously identified cellular oncogene addictions in PEL cell lines, including MCL1. MCL1 is a member of the BCL2 family, which functions to prevent intrinsic apoptosis and has been implicated in several cancers. Despite the overlapping functions of the BCL2 family members, PEL cells are dependent only on MCL1, suggesting that MCL1 may have nonredundant functions. To investigate why PEL cells exhibit selective addiction to MCL1, we inactivated the intrinsic apoptosis pathway by engineering BAX/BAK1 double knockout cells. In this context, PEL cells become resistant to MCL1 knockdown or MCL1 inactivation by the MCL1 inhibitor S63845, indicating that the main function of MCL1 in PEL cells is to prevent BAX/BAK1-mediated apoptosis. The selective requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Ectopic expression of several BCL2 family proteins, as well as the KSHV BCL2 homolog, significantly decreased basal caspase 3/7 activity and buffered against staurosporine-induced apoptosis. Finally, overexpressed BCL2 family members can functionally substitute for MCL1, when it is inhibited by S63845. Together, our data indicate that the expression levels of the BCL2 family likely explain why PEL tumor cells are highly addicted to MCL1. Importantly, our results suggest that caution should be taken when considering MCL1 inhibitors as a monotherapy regimen for PEL because resistance can develop easily. IMPORTANCE Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. We showed previously that PEL cell lines require the antiapoptotic protein MCL1 for survival but not the other BCL2 family proteins. This selective dependence on MCL1 is unexpected as the BCL2 family functions similarly in preventing intrinsic apoptosis. Recently, new roles for MCL1 not shared with the BCL2 family have emerged. Here, we show that noncanonical functions of MCL1 are unlikely essential. Instead, MCL1 functions mainly to prevent apoptosis. The specific requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Consistent with this model, shifting these expression ratios changes the requirement away from MCL1 and toward the dominant BCL2 family gene. Together, our results indicate that although MCL1 is an attractive chemotherapeutic target to treat PEL, careful consideration must be taken, as resistance to MCL1-specific inhibitors easily develops through BCL2 family overexpression.

Health Disparities Among Hispanics With Rheumatoid Arthritis: Delay in Presentation to Rheumatologists Contributes to Later Diagnosis and Treatment.

OBJECTIVE: The aim of this study was to evaluate referral and treatment delays by ethnicity/race in patients with rheumatoid arthritis (RA) treated at an academic rheumatology center. METHODS: We reviewed the medical records of all RA patients evaluated at an outpatient clinic between 2011 and 2016 to identify newly diagnosed and naive-to-treatment patients. We determined the durations between symptom onset and first rheumatology visit and time to initiate treatment. Data extraction included referral source, demographics, treatment, and laboratory tests. Routine use of a multidimensional health assessment questionnaire allowed us to calculate baseline RAPID3 (routine assessment of patient index data 3) scores. Comparisons between self-reported ethnicity/race groups were performed. We used logistic regression models to analyze associations between baseline variables and early referral. RESULTS: Data from 152 disease-modifying antirheumatic drug-naive RA patients were included in the study; 35% were white, 37% black, 20% Hispanic, and 8% other. The range in median time to first rheumatology visit was 6 to 8 months for all patient groups, except Hispanic. This group had a median time of 22.7 months (p = 0.01). The referral pattern was considerably variable between-groups; 40% of Hispanic patients were self-referred (p = 0.01). There were no statistically significant between-group differences for time to treatment initiation according to ethnicity/race. RAPID3 scores (p = 0.04) and erythrocyte sedimentation rates (p = 0.01) were significantly higher in the black and Hispanic groups. A high C-reactive protein value at baseline was associated with earlier referral. CONCLUSIONS: There is significant delay in initial presentation to a rheumatologist that was associated with a higher disease severity at presentation, especially for Hispanic patients.

Marginal discrepancy dimensions of single unit metal crowns fabricated by using CAD-CAM-milled acrylate resin polymer blocks or a conventional waxing technique.

STATEMENT OF PROBLEM: Because crowns with open margins are a well-known problem and can lead to complications, it is important to assess the accuracy of margins resulting from the use of a new technique. Currently, data regarding the marginal fit of computer-aided design and computer-aided manufacturing (CAD-CAM) technology to fabricate a complete gold crown (CGC) from a castable acrylate resin polymer block are lacking. PURPOSE: The purpose of this in vitro study was to compare marginal discrepancy widths of CGCs fabricated by using either conventional hand waxing or acrylate resin polymer blocks generated by using CAD-CAM technology. MATERIAL AND METHODS: A plastic model of a first mandibular molar was prepared by using a 1-mm, rounded chamfer margin on the entire circumference of the tooth. The master die was duplicated 30 times, and 15 wax patterns were fabricated by using a manual waxing technique, and 15 were fabricated by using CAD-CAM technology. All patterns were invested and cast, and resulting CGCs were cemented on their respective die by using resin-modified glass ionomer cement. The specimens were then embedded in acrylic resin and sectioned buccolingually. The buccal and lingual marginal discrepancies of each sectioned portion were measured by using microscopy at ×50 magnification. Data were subjected to repeated measures 2-way ANOVA, by using the Tukey post hoc pairwise comparison test (α=.05). RESULTS: The factor of "technique" had no significant influence on marginal discrepancy measurement (P=.431), but a significant effect of "margin location" (P=.019) was noted. The confounding combination of factors was found to be significantly lower marginal discrepancy dimensions of the lingual margin discrepancy than on the buccal side by using CAD-CAM technology. CONCLUSIONS: The marginal discrepancy of CAD-CAM acrylate resin crowns was not significantly different from those made with a conventional manual method; however, lingual margin discrepancies present from CAD-CAM-prepared crowns were significantly less than those measured on the respective buccal surface.

Perceptions of Ambulatory Workflow Changes in an Academic Primary Care Setting.

As health care moves to a value-based system, the need for team-based models of care becomes increasingly important to adequately address the growing number of clinical quality metrics required of health care providers. Finding ways to better engage certified medical assistants (CMAs) in the process allows providers to focus on more complex tasks while improving the efficiency of each office visit. Although the roles and responsibilities for CMAs across the specialties can vary widely, standardizing the work can be a helpful step in scaling best practices across an institution. This article presents the results of a survey that evaluated various components of a CMA workflow in adult primary care practices within an academic medical center. Although the survey identified improved engagement and satisfaction with standardized changes overall, it also showed time constraints and provider discretion forcing unplanned modifications. Reviewing and reconciling medications seemed to be the most challenging for CMA staff, leading us to reconsider their involvement in this aspect of each visit. It will be important to continue innovating and testing team-based care models to keep up with the demands of a quality-based health care system.

Interventions of an Academic Medical Center to Improve Likelihood to Recommend.

Improved patient satisfaction is correlated with improved adherence and health outcomes for patients and financial performance for health care organizations. Increasingly, efforts are being made to measure and optimize patient satisfaction by both providers and insurers. Researchers investigated whether specific changes in staff interaction with patients would improve patients' likelihood to recommend a practice. There were 4 separate initiatives implemented by the medical staff and providers at 14 unique practice sites. At these sites, patients' satisfaction was measured 9 weeks prior to the initiative and then for 9 weeks after to assess impact on patients' likelihood to recommend the practice. Each of the 4 initiatives demonstrated improved patient satisfaction, whereas 2 reached statistical significance. These interventions demonstrated a rise in likelihood to recommend the practice score from 78.6% (33rd percentile) to 83.1% (68th percentile) in all of the combined practices.

The Mitochondrial Ubiquitin Ligase MARCHF5 Cooperates with MCL1 to Inhibit Apoptosis in KSHV-Transformed Primary Effusion Lymphoma Cell Lines.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several malignancies in people with HIV including Kaposi's sarcoma and primary effusion lymphoma (PEL). We have previously shown that PEL cell lines require myeloid cell leukemia-1 (MCL1) to inhibit apoptosis. MCL1 is an oncogene that is amplified in cancers and causes resistance to chemotherapy regimens. MCL1 is thus an attractive target for drug development. The emerging clinical relevance and therapeutic potential of MCL1 motivated us to study the roles of this oncogene in PEL in depth. Using a systems biology approach, we uncovered an unexpected genetic interaction between MCL1 and MARCHF5 indicating that they function in the same pathway. MARCHF5 is an E3 ubiquitin ligase most known for regulating mitochondrial homeostasis and antiviral signaling, but not apoptosis. We thus investigated how MCL1 and MARCHF5 cooperate to promote PEL cell survival. CRISPR knockout (KO) of MARCHF5 in PEL cell lines resulted in a significant increase in apoptosis despite the presence of MCL1. The anti-apoptotic function of MARCHF5 was dependent on its E3 ligase and dimerization activities. Loss of MARCHF5 or inhibition of the 26S proteasome furthermore stabilized the MCL1 antagonist NOXA without affecting levels of MCL1. Interestingly, NOXA KO provides a fitness advantage to PEL cells suggesting that NOXA is the pro-apoptotic signal that necessitates the anti-apoptotic activities of MCL1 and MARCHF5. Finally, endogenous reciprocal co-immunoprecipitation experiments show that MARCHF5 and NOXA are found in the same protein complex. Our findings thus provide the mechanistic link that underlies the genetic interaction between MCL1 and MARCHF5. We propose that MARCHF5 induces the degradation of the MCL1 antagonist NOXA thus reinforcing the pro-survival role of MCL1 in these tumor cells. This newly appreciated interaction of the MCL1 and MARCHF5 oncogenes may be useful to improve the design of combination therapies for KSHV malignancies.

Results of an initiative to charge for previously uncompensated care in an academic primary care practice.

Increasing clinical workload with dwindling compensation has challenged primary care medical practices over the past decade. This has led to more physicians leaving and fewer medical trainees entering primary care. In an effort to make primary care practices viable, many groups routinely charge for providing care that was uncompensated in the past. We initiated a program in our practice that charged for certain after-hour and electronic communications, completion of forms outside of office visits, and failure to show for appointments. We assessed the effect on workload, patient adherence to appointments, and financial outcomes. This initiative decreased our physicians' workload, increased physicians' satisfaction, and produced a modest increase in revenues.

Utilizing the Regional Acceleratory Phenomenon and Dental Implant Anchorage for Distalization and Intrusion of a Mesially Tipped Mandibular Molar: A Case Report.

INTRODUCTION: Introduction of a surgical insult in conjunction with orthodontic therapy has been shown to accelerate treatment in minor tooth movement and comprehensive orthodontic cases by induction of the regional acceleratory phenomenon (RAP). When applying this concept to a molar tipped into an adjacent edentulous site, a dental implant can be planned to anchor the movement. CASE PRESENTATION: A generally and periodontally healthy 25-year-old patient presented missing tooth #19, with tooth #18 mesially tipped into the first molar crown space. A dental implant was placed in the #19 position. Following osseointegration, the implant anchored orthodontic movement of the adjacent tooth, which was initiated in conjunction with third molar extraction. CONCLUSION: Favorable biomechanics for molar uprighting can be achieved using an osseointegrated implant and a customized orthodontic device. The presented technique facilitates implant site development without delaying placement of the fixture and simplifies fabrication of a harmonious and anatomic implant-supported restoration. Induction of the RAP may hasten treatment completion.

Fracture necrosis: A risk indicator for tooth loss.

BACKGROUND AND OVERVIEW: The term "fracture necrosis" has been used to describe the condition found in a minimally restored tooth without a history of trauma when the suspected etiology for the loss of pulpal vitality is a crown-originating fracture. Teeth with fracture necrosis have a poor prognosis, and, when accompanied by characteristic radiographic findings, extraction may be considered the primary treatment option. CASE DESCRIPTIONS: Two adult men with crown-originating fractures and suspected fracture necrosis had localized periodontal bone and attachment loss associated with severe pain on mastication from mandibular second molars. In case 1, the patient desired to retain the tooth despite an unfavorable prognosis. Nonsurgical root canal therapy and a crown prolonged tooth survival for only 30 months. The patient in case 2 requested extraction after a thorough review of his dental condition and tooth prognosis. CONCLUSIONS: A tooth with fracture necrosis may continue to harbor virulent microorganisms after root canal therapy. When these microorganisms have access to the periodontal attachment, progressive loss of supporting tissues can be expected. PRACTICAL IMPLICATIONS: When weighing treatment options for teeth with fracture necrosis associated with characteristic radiographic findings, preference toward extraction and tooth replacement, rather than treatment aimed at tooth retention, may represent a sound clinical approach.

Focus on Epithelialized Palatal Grafts. Part 2: Implant Site Development.

INTRODUCTION: The epithelialized palatal graft (EPG), introduced in 1963, has persisted as the gold standard for gingival augmentation, and in the present era, mucosal augmentation around dental implants has become an important concern. A limited body of evidence suggests peri-implant mucosal augmentation may favorably impact bone and mucosal stability and peri-implant health under some circumstances. Although more contemporary procedures for peri-implant mucosal augmentation are often preferred based on convenience and esthetic considerations, EPG augmentation at dental implant sites is distinguishable from methods which do not deepen the vestibule and eliminate unfavorable superficial soft tissue. Implant sites augmented with EPG are qualitatively distinct from sites augmented using other methods. CASE SERIES: Seven generally healthy patients received EPG augmentation before dental implant placement, at implant placement, before implant uncovering, or after implant uncovering. In each case, the patient exhibited a favorable zone of attached peri-implant mucosa following treatment. CONCLUSIONS: Reliable mucosal augmentation with EPG is achievable at multiple phases in the course of dental implant therapy. EPG augmentation offers distinct clinical advantages and may be preferable to other mucosal augmentation strategies at some dental implant sites.

Patient-directed intervention versus clinician reminders alone to improve aspirin use in diabetes: a cluster randomized trial.

BACKGROUND: Physician-directed approaches have not eliminated the underuse of effective preventive therapies. METHODS: In a cluster-randomized design, 19 physicians caring for 334 eligible patients at least 40 years of age were randomized. All clinicians received computerized reminders at office visits. Intervention physicians received e-mails asking whether aspirin was indicated for each patient. If so, patients received a mailing and nurse telephone call addressing aspirin. The primary outcome was self-reported regular aspirin use. RESULTS: Outcome assessment telephone interviews were completed for 242 (72.5%) patients. At follow-up, aspirin use was reported by 60 (46%) of the 130 intervention patients and 44 (39%) of the 112 reminder-only patients, a nonsignificant 7.2% difference (95% confidence interval: -3.9 to 18 percentage points, p = .20). In the subgroup reporting no aspirin use at baseline and no contraindications, 33 (43%) of the 76 intervention and 22 (30%) of the 74 reminder-only patients used aspirin, a 10% difference accounting for clustering (95% CI: 2.2 to 18 percentage points, p = .013). DISCUSSION: A patient-directed intervention modestly increased aspirin use among diabetes patients beyond that achieved using computerized clinician reminders for ideal candidates. Obstacles included difficulty contacting patients, real or perceived contraindications, and failure to follow the nurse's advice.

Use of an electronic medical record to detect patients at high risk of metformin-induced lactic acidosis.

The Notes section welcomes the following types of contributions: (1) practical innovations or solutions to everyday practice problems, (2) substantial updates or elaborations on work previously published by the same authors, (3) important confirmations of research findings previously published by others, and (4) short research reports, including practice surveys, of modest scope or interest. Notes should be submitted with AJHP's manuscript checklist. The text should be concise, and the number of references, tables, and figures should be limited.

Medication dosing errors for patients with renal insufficiency in ambulatory care.

BACKGROUND: Approximately 8.7 million (3%) Americans have various degrees of chronic renal insufficiency (CRI). Patients with CRI are susceptible to adverse drug events related to improper dose adjustment of drugs that are eliminated primarily unchanged through the kidney. Renal dosing errors are an important quality-of-care problem in the inpatient setting, yet little is known about dosing errors for patients with renal insufficiency in the outpatient setting. METHODS: Electronic records were queried to identify patients with CRI (estimated creatinine clearance < 50 mL/min) who visited the ambulatory care clinic at least once from January 1, 2003 through December 31, 2003. RESULTS: Of the total of 224 patients identified with CRI, 157 (70%) received one or more of 17 drugs with high rates of renal elimination. A total of 207 drugs requiring dose adjustment were prescribed to these patients, and 52 (25%) were prescribed at an inappropriately high dose. For 127 (57%) of the 224 patients, CRI was not documented. Patients with documented CRI were equally likely to be prescribed an inappropriately high dose of a target drug. DISCUSSION: Incorrect dosing of medications among patients with CRI is common in the ambulatory care setting. Strategies for preventing medication dosing errors can target the prescribing and monitoring stages of pharmaceutical care.

Dietary differences among women of Polish descent by country of birth and duration of residency in the United States.

OBJECTIVES: Changes in breast and gastric cancers and coronary artery disease among people of Polish descent after migration to the United States suggest there may be potentially modifiable factors affecting incidence of these diseases. We examined relationships of dietary factors associated with these diseases with stage of migration among Polish women in Chicago. DESIGN: Women of Polish descent (N = 396) were selected from Polish women's social organizations. Women completed a modified Health Habits and History Questionnaire. SETTING: The questionnaire was completed either at the participant's home or at a Polish social organization. PARTICIPANTS: Participants ranged in age from 17-81 years, and included women born in Poland or the United States, who had at least one parent of Polish. INTERVENTIONS: Participants were stratified by country of birth and migration period (1935-1979, 1980-1989, 1990-1997). MAIN OUTCOME MEASURES: The average daily intake of food groups and nutrients was assessed using multiple linear regression. RESULTS: We found statistically significant differences by birth country for 19 of 34 nutrients, 4 of 7 food groups, and for 21 nutrients, and 5 food groups among the different migration tertiles. CONCLUSIONS: Women from Poland and more recent migrants had generally more nutritious intakes, compared to US-born women, or earlier migrants. APPLICATIONS/CONCLUSIONS: There are significant dietary differences among women of Polish descent that vary by duration of US residency and birth country. Women with dietary intakes which place them at higher risk for cancers and cardiovascular disease could be targeted for interventions to lower their disease risk.

Can electronic health records help improve patients' understanding of medications?

OBJECTIVES: To present pilot data from an ongoing electronic health record (EHR) quality improvement study to improve medication management using patient previsit review of the EHR medication list and a plain-language new medication information sheet to provide with every new EHR prescription. STUDY DESIGN: Postvisit survey of 191 patients at an academic general internal medicine clinic. METHODS: Patients were asked about discrepancies and problems, concerns, and questions (PCQs) in their EHR summary for up to 10 current medications and about knowledge of new prescriptions. Findings describe the extent of medication discrepancies, perceived PCQs about current medications, and patient knowledge about new medications. RESULTS: Overall, 78.0% of patients had at least 1 discrepancy, more than half had a drug listed that they were not taking or dose or frequency discrepancies, and 8.9% reported an omission; 41.9% indicated at least 1 PCQ about their current medications. Among patients who received a new prescription, most knew what the new medication was for and how to take it. However, 66.0% indicated uncertainty about potential adverse effects that they should telephone the physician about. CONCLUSIONS: Discrepancies can be efficiently categorized by previsit review of EHR medication lists. Prereview offers physicians the opportunity to better address important medication PCQs. Testing the value of EHR-generated plain-language medication information sheets requires follow-up interviews after medications are filled. Patients may not understand the actual benefits of new medications.

Frequency of failure to inform patients of clinically significant outpatient test results.

BACKGROUND: Failing to inform a patient of an abnormal outpatient test result can be a serious error, but little is known about the frequency of such errors or the processes for managing results that may reduce errors. METHODS: We conducted a retrospective medical record review of 5434 randomly selected patients aged 50 to 69 years in 19 community-based and 4 academic medical center primary care practices. Primary care practice physicians were surveyed about their processes for managing test results, and individual physicians were notified of apparent failures to inform and asked whether they had informed the patient. Blinded reviewers calculated a "process score" ranging from 0 to 5 for each practice using survey responses. RESULTS: The rate of apparent failures to inform or to document informing the patient was 7.1% (135 failures divided by 1889 abnormal results), with a range of 0% to 26.2%. The mean process score was 3.8 (range, 0.9-5.0). In mixed-effects logistic regression, higher process scores were associated with lower failure rates (odds ratio, 0.68; P < .001). Use of a "partial electronic medical record" (paper-based progress notes and electronic test results or vice versa) was associated with higher failure rates compared with not having an electronic medical record (odds ratio, 1.92; P = .03) or with having an electronic medical record that included both progress notes and test results (odds ratio, 2.37; P = .007). CONCLUSIONS: Failures to inform patients or to document informing patients of abnormal outpatient test results are common; use of simple processes for managing results is associated with lower failure rates.

Improving medication reconciliation in the 21st century.

Approximately 7000 deaths occur yearly in the United States as a result of medication errors, and 1.5 million people are harmed by adverse drug events at a cost of $3.5 billion per year. Computerized order entry has been shown to decrease the number of medication errors by 55% to 80 % in the hospital. This has led many to advocate the use of electronic medical records in both the inpatient and outpatient setting. However, there is little evidence at present that electronic medical records reduce adverse drug events in the outpatient setting. This may be largely due to the quality of medication lists in the medical record: Among complicated patients, complete agreement between the medication list and what the patient is actually taking occurs in only 5% of patients. Unless there is improved medication reconciliation, it will be difficult to realize the potential safety benefits of information technology. An accurate medication list requires a healthcare team dedicated to obtaining and maintaining this information.

A clinical investigation of the fit of removable partial dental prosthesis clasp assemblies.

STATEMENT OF PROBLEM: Removable partial denture frameworks are complex castings fabricated from high-shrinkage alloys. This may result in difficulty in achieving accurate fit. PURPOSE: The purpose of this study was to evaluate which component(s) of the clasp assembly contact the abutment tooth clinically. MATERIAL AND METHODS: New and existing frameworks with at least 1 conventional prepared occlusal rest were evaluated for fit. The spacing between the bottom of each of the rests of the 50 clasp assemblies and the corresponding rest seat were recorded with vinyl polysiloxane. The fit of each rest was determined with the use of a dial caliper by measuring, in micrometers, the thickness of the record between the rest and the bottom of the rest seat. The Kennedy classification was also recorded. A 2-sample t test was used to evaluate the difference in fit between tooth-tissue supported and tooth-supported designs (alpha=.05). RESULTS: The average space between the rest and prepared rest seat was 193 +/- 203 microm, with a range of 0 to 828 mum. Twenty tooth-tissue frameworks had an average space of 136 +/- 160 microm and 30 tooth-supported frameworks had an average space of 230 +/- 222 microm. The 2-sample t test showed no significant difference for fit between tooth-tissue supported and tooth-supported frameworks (P=.1081). Twenty-four percent of rests had contact in the prepared rest seat. CONCLUSION: The majority of rests evaluated did not contact the intended surfaces.

The genetic family history as a risk assessment tool in internal medicine.

PURPOSE: The study goals were to (1) determine the proportion of unselected individuals at increased risk for diseases with known genetic components and (2) compare the documentation and quality of risk assessment between a questionnaire, a pedigree interview, and chart review. METHODS: Seventy-eight patients seen in a division of internal medicine were randomized into two groups, which completed a questionnaire or underwent a pedigree interview. Chart notes were compared to both study tools. RESULTS: Sixty-two (79.5%) of the 78 participants scored at increased risk for at least one category. Either of the two study tools found significantly more people at high risk (48/78, 61.5%) than the chart review (31/78, 39.7%) (P = 0.01). CONCLUSIONS: Approximately 20% of patients in an unselected internal medicine practice were at an increased risk that was not documented in reviewed chart notes. Targeted family history analysis reveals patients who require increased medical surveillance, preventive measures, or genetic counseling/testing.