This is the January 2016 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing Cryptococcus Alkaline Extracts
A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains of C. neoformans and C. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4(+) T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine.
IMPORTANCE: The encapsulated yeast Cryptococcus neoformans and its closely related sister species, Cryptococcus gattii, are major causes of morbidity and mortality, particularly in immunocompromised persons. This study reports on the preclinical development of vaccines to protect at-risk populations from cryptococcosis. Antigens were extracted from Cryptococcus by treatment with an alkaline solution. The extracted antigens were then packaged into glucan particles, which are hollow yeast cell walls composed mainly of β-glucans. The glucan particle-based vaccines elicited robust T cell immune responses and protected mice from otherwise-lethal challenge with virulent strains of C. neoformans and C. gattii. The technology used for antigen extraction and subsequent loading into the glucan particle delivery system is relatively simple and can be applied to vaccine development against other pathogens.
Until recently, a diagnosis of peritoneal carcinomatosis was uniformly accompanied by a grim prognosis that was typically measured in weeks to months. Consequently, the management of carcinomatosis revolves largely around palliation of symptoms such as bowel obstruction, nausea, pain, fatigue, and cachexia. A prior lack of effective treatment options created the nihilistic view that currently exists and persists despite improvements in the efficacy of systemic therapy and the evolution of multimodality approaches including surgery and intraperitoneal chemotherapy. This article reviews the evolution and current state of treatment options for patients with peritoneal carcinomatosis. In addition, it highlights recent advances in understanding the molecular biology of carcinomatosis and the focus of current and future clinical trials. Finally, this article provides practical management options for the palliation of common complications of carcinomatosis. It is hoped that the reader will recognize that carcinomatosis is no longer an imminent death sentence and that through continued research and therapeutic innovation, clinicians can make an even greater impact on this form of metastatic cancer.
A lack of techniques to image multiple genomic loci in living cells has limited our ability to investigate chromosome dynamics. Here we describe CRISPRainbow, a system for labeling DNA in living cells based on nuclease-dead (d) Cas9 combined with engineered single guide RNA (sgRNA) scaffolds that bind sets of fluorescent proteins. We demonstrate simultaneous imaging of up to six chromosomal loci in individual live cells and document large differences in the dynamic properties of different chromosomal loci.
NeuN(+) neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure
Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN(+) nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.
Background: The Implicit Association Test (IAT) is a well-researched method of identifying an individual's implicit bias. Occurring outside of conscious awareness, implicit bias manifests itself in the form of nonverbal thoughts, behaviors and actions that influence an individual and that are suggestive of unequal treatment. In the undergraduate medical education curriculum, the IAT is commonly used to assess the medical students' personal bias. Studies from the American Association of Medical Colleges (AAMC) have shown that bias is ranked highly as one of the least addressed educational goals in medical education and training. The medical literature suggests that implicit bias affects how clinical faculty make patient care decisions, and that this in turn affects medical student education. Data collected from our medical school's first year curriculum suggest that there are missed opportunities to explore the effects of bias on health outcomes.
Objective: The purpose of this study was to analyze comments in reflection papers submitted by students enrolled in the required Determinants of Health (DoH) course during the Fall 2014- Spring 2015 curriculum at the University of Massachusetts Medical School (UMMS). The DoH course assignment asked students to select a reading, experience in taking the IAT or class discussion, and comment on how the material led to new insight about the potential effect of biases or stereotyping on future clinical decisions. The themes from this analysis provided context for relevant areas for further exploration of the impact of implicit bias in medical education.
Method: 125 first-year medical students (48% female, 52% male; mean age 25 years; 95% from Massachusetts, 9% identified as under-represented ethnic/racial minorities) in the entering class of 2014 submitted written reflections following attendance and discussion-based learning in the DoH course. Grounded theory methodology was used for the qualitative analysis of the comments. Papers were de-identified, read, and codes were constructed according to emerging themes (descriptive, diagnostic, and prescriptive) found.
The codebook development focused on "bias," "systemic/institutional bias," "individual bias," "awareness" and "health disparities". Student commentary was coded for themes and tallied for total amount of discussion for each theme. Inter-rater reliability was calculated for 20% of the sample using Cohen's kappa.
Results: The following themes emerged: 1) an understanding of the IAT and the results of the IAT; 2) a definition of bias; 3) a suggestion of source of bias; 4) factors informing bias; and 5) action items to combat the effects of implicit bias on future physicians. Ninety-five of 125 students' comments (76%) mapped to descriptive themes associated with bias; 27% (n=26/95) of comments suggested all individuals have bias; 57% (n=55) of comments suggested potential sources of bias, ranging from cultural and community upbringings to societal media; 83% (n=79) of comments focused on the negative effect implicit bias can have on decision-making in patient care; and nearly 96% (n=91) of comments felt that acknowledging their own implicit bias would benefit their interactions with patients in their future medical careers. Additionally, 58% (n=73/125) of students' comments noted that making a conscious effort to self-reflect and address bias would improve decision-making, and 32% (n=40) of comments noted it was a physician's responsibility to dismantle the bias found in the healthcare system (15 comments suggested this happen through avenues such as advocacy and legislation). Seventy students' comments (56%) mapped to comments discussing the lAT. Forty-three percent (n=30) comments noted students surprised by their results and 29% (n=20) of comments suggested that the student was not surprised. While 75 students (60%) did not comment on their reaction, the IAT sparked self-reflection of implicit bias and its origin in 68 of these students, and 16% (n=20) of comments found the IAT to be a valuable tool in identifying implicit bias.
With regard to the current climate ofhealthcare, 40 responding students (32%) identified racism or racial bias existing within the medical field, noting potential sources of racism including lack of trust in physicians from historical events such as the Tuskegee Syphilis Experiment and societal inequalities as a whole. Additionally, 29 students' comments (23%) mentioned systemic/institutional bias as potentially having an impact on individual bias and vice versa.
Conclusions: The use of the IAT in the medical education curriculum is informative and the medical student response to it is impactful. Medical students gain insight into the importance of understanding personal implicit bias and the effect it may have on clinical decision-making through courses such as Determinants of Health. Students have the ability and the desire to identify and self-reflect on the development of behaviors and skills that will facilitate improved decision-making in the care of patients, and improved patient interactions. This analysis also points to the significance of further exploration of faculty involvement in these topics to further engage medical students throughout their undergraduate medical training. As over 93% of the first-year medical school courses did not utilize race identifiers and non-medical factors in clinical vignettes, this is another opportunity to apply real-life scenarios to the educational curriculum.
The Incidence of Malignancy and the Preoperative Assessment of Women Undergoing Hysterectomy with Morcellation for Benign Indications
Background: The use of power morcellation in gynecologic surgery has come under scrutiny secondary to concerns for occult malignancy dissemination. The incidence of undiagnosed gynecologic malignancy when hysterectomy performed for benign indications is not definitive but has been quoted as high as 2.7% (1:37). There is not a standard recommended preoperative evaluation, and variation is anticipated by preoperative complaint or diagnosis.
Objectives: To quantify the malignancy incidence in women undergoing hysterectomy for benign indications and to compare the preoperative evaluation of patients undergoing hysterectomy with and without morcellation.
Methods: Retrospective cohort of women undergoing hysterectomies between October 2007 and June 2014 was identified by procedural codes through the hospital billing system. Exclusions included hysterectomies performed by gynecologic oncologists or non-gynecologic surgeons and surgeries performed outside the UMass healthcare system. Chart abstraction included demographics; pre-hysterectomy evaluation, including current cervical cytology, pathologic endometrial assessment (biopsy, dilation and curettage), and imaging (ultrasound, MRI, CT scan, sonohysterogram, or hysteroscopy); intraoperative factors; and final diagnosis.
Results: Analytic cohort included 2,332 women undergoing hysterectomy with 396 (17.0%) including use of morcellation. The malignancy incidence on final pathology was 2.1% and was different between non-morcellated versus morcellated specimens (2.5% vs. 0.3%, p<0.001). Intraoperative gynecologic oncology consults and/or frozen pathologic evaluations were performed in 1.2% (n=27) and 5.4% (n=126) of cases, respectively. There was no significant difference in current cervical cytology (68.9% vs. 71.3%) and imaging (39.6% vs. 34.9%) rates between the non- versus morcellated groups; however, those experiencing morcellation were less likely to have preoperative pathologic endometrial assessment (21.7% vs. 34.2%, p<0.001).
Conclusion: The incidence of malignancy at time ofhysterectomy performed by non-oncology trained gynecologists was 2.1% overall, and 0.3% in morcellated cases. The pre-operative evaluation of patients undergoing hysterectomy with morcellation is similar to those without morcellation, except for lower rates of pathologic endometrial assessment. An argument could be made that a pathology assessment is indicated in this group due to risk of dissemination in the case of occult malignancy. The risk of occult malignancy is rare, but this should be discussed with patients and taken into account during the pre-operative evaluation.
BACKGROUND AND OBJECTIVES: Reflective writing in medicine allows for the opportunity to analyze, interpret, and learn from clinical experiences. The purpose of this study was to evaluate the beneficial effects of reflective reading and writing for a department using a weekly listserve.
METHODS: The Department of Family Medicine and Community Health at the University of Massachusetts Medical School sends out a weekly reflective writing story written by its members to celebrate clinical/teaching success. We conducted a 19-item questionnaire in the summer of 2014 among all 402 members.
RESULTS: Questionnaires were completed by 161 of 402 (40%) readers and 50 of 122 (41%) writers. Readers found many benefits; 84% reported learning "a lot" about how a colleague handled a certain clinical situation, while 79% found that the reflective writing listserve helped them feel more connected to colleagues. A total of 83% reported that reading the weekly story positively affected their empathy and patient centeredness. Those who reported reading the stories most often were more likely to report achieving the most benefits. The majority of respondents who wrote stories agreed with all suggested benefits of writing; 73% reported that writing allowed them to celebrate a patient/research/teaching encounter that they were proud of, and 72% reported that it gave them better perspective or clarity about a patient experience "a lot" of the time.
CONCLUSIONS: As departments struggle with provider burnout and feelings of being overwhelmed and disconnected, strategies like a reflective writing listserve may be a means to improve support and inspire clinicians and learners to feel fulfilled.
Leaving the room, I marveled at what we learn when we create the space to allow our patients to tell us their stories, to show us what they need and to teach us how they adapt. I was reminded how much easier it is to listen than to write and un-write my own stories about them.
Relationship between self-assessed and tested non-English-language proficiency among primary care providers
BACKGROUND: Individuals with limited English proficiency experience poor patient-clinician communication. Most studies of language concordance have not measured clinician non-English-language proficiency.
OBJECTIVES: To evaluate the accuracy of the self-assessment of non-English-language proficiency by clinicians compared with an oral proficiency interview.
SUBJECTS: Primary care providers (PCPs) in California and Massachusetts.
MEASURES: PCPs first completed a self-assessment of non-English-language proficiency using a version of the Interagency Language Roundtable (ILR) Scale, followed by the Clinician Cultural and Linguistic Assessment (CCLA), a validated oral proficiency interview. We used nonparametric approaches to analyze CCLA scores at each ILR scale level and the correlation between CCLA and ILR scale scores.
RESULTS: Sixteen PCPs in California and 51 in Massachusetts participated (n=67). Participants spoke Spanish (79%), followed by Cantonese, Mandarin, French, Portuguese, and Vietnamese. The respondents self-assessed as having "excellent" proficiency 9% of the time, "very good" proficiency 24% of the time, "good" proficiency 46% of the time, "fair" proficiency 18% of the time, and "poor" proficiency 3% of the time. The average CCLA score was 76/100. There was a positive correlation between self-reported ILR scale and CCLA score (sigma=0.49, P < 0.001). The variance in CCLA scores was wider in the middle categories than in the low or high ILR categories (P=0.003).
CONCLUSIONS: Self-assessment of non-English-language proficiency using the ILR correlates to tested language proficiency, particularly on the low and high ends of the scale. Participants who self-assess in the middle of the scale may require additional testing. Further research needs to be conducted to identify the characteristics of PCP whose self-assessments are inaccurate and, thus, require proficiency testing.
Behind bars: the compelling case for academic health centers partnering with correctional facilities
Academic health centers (AHCs), particularly those that are publicly funded institutions, have as their mission the treatment of disadvantaged populations, the training of the next generation of clinicians, and the development and dissemination of new knowledge to reduce the burden of disease and improve the health of individuals and populations. Incarcerated populations have the most prevalent and acute disease burden and health disparities in the United States, even in comparison with inner-city populations. Yet, only a small proportion of AHCs have reached out to incarcerated populations to fulfill their mission. Those AHCs that have partnered with correctional facilities have overcome concerns about the value and popularity of "training behind bars"; the cost, liability, and pragmatics of caring for a medically complicated population; and the viability of correctional health research and extramural research funding. They have done so to great benefit to patients, students, and faculty. Partnering with correctional facilities to provide health care offers opportunities for AHCs to fulfill their core missions of clinical service, education, and research, while also enhancing their financial stability, to the benefit of all. In this Commentary, the authors discuss, based on their experiences, these concerns, how existing partnerships have overcome them, and the benefits of such relationships to both AHCs and correctional facilities.
The New Zealand (NZ) government has set a goal to reduce smoking prevalence to 5% by 2025. Furthermore, it wants to achieve this for all population groups, even though current smoking prevalences are significantly higher (45%) among Māori (indigenous New Zealanders), Pacific peoples (31%) and those living in the most deprived neighborhoods (38%). Data from the NZ Year 10 smoking survey indicate that girls develop addiction faster than boys. Using data from the 2002 and 2003 Year 10 surveys we examined differences in the speed of onset of tobacco addiction between youth of Asian, European, Māori and Pacific Island origins.
The Nicotine Dependence in Teens (NDIT) study is a prospective cohort investigation of 1294 students recruited in 1999-2000 from all grade 7 classes in a convenience sample of 10 high schools in Montreal, Canada. Its primary objectives were to study the natural course and determinants of cigarette smoking and nicotine dependence in novice smokers. The main source of data was self-report questionnaires administered in class at school every 3 months from grade 7 to grade 11 (1999-2005), for a total of 20 survey cycles during high school education. Questionnaires were also completed after graduation from high school in 2007-08 and 2011-12 (survey cycles 21 and 22, respectively) when participants were aged 20 and 24 years on average, respectively. In addition to its primary objectives, NDIT has embedded studies on obesity, blood pressure, physical activity, team sports, sedentary behaviour, diet, genetics, alcohol use, use of illicit drugs, second-hand smoke, gambling, sleep and mental health. Results to date are described in 58 publications, 20 manuscripts in preparation, 13 MSc and PhD theses and 111 conference presentations. Access to NDIT data is open to university-appointed or affiliated investigators and to masters, doctoral and postdoctoral students, through their primary supervisor (www.nditstudy.ca). behalf of the International Epidemiological Association.
The majority of tobacco use emerges in individuals before they reach 21 years of age, and many adult distributors of tobacco to youths are young adults aged between 18 and 20 years. Raising the tobacco sales minimum age to 21 years across the United States would decrease tobacco retailer and industry sales by approximately 2% but could contribute to a substantial reduction in the prevalence of youths' tobacco use and dependency by limiting access.
This review will describe the biological and behavioral aspects of nicotine addiction as it develops during adolescence and advances over a lifetime. Symptoms of physical nicotine dependence typically appear when adolescents are smoking only a few cigarettes each month. Physical dependence develops through a set sequence of symptoms that correlate with changes in brain structure in addiction circuits. Smokers often describe their symptoms of physical dependence as "wanting," then "craving," and eventually "needing" to smoke. These symptoms appear whenever the smoker goes too long without smoking. The intensity of abstinence-induced craving correlates with spontaneous activation of addiction-related networks in the brain as illustrated in the graphical abstract of this article. Initially, smoking a single cigarette can keep withdrawal symptoms at bay for weeks, but as tolerance develops, cigarettes must be smoked at progressively shorter intervals to suppress withdrawal symptoms. The physiologic need to repeatedly self-administer nicotine at shorter intervals explains a full spectrum of addictive symptoms and behaviors.
In a neighborhood near you: how community health workers help people obtain health insurance and primary care
Implementing the health insurance mandate of the Patient Protection and Affordable Care Act (ACA), signed into law in 2010, will require states to reach, educate, and successfully enroll individuals and families who have had little experience with health coverage. The uninsured are likely to require considerable individualized application and enrollment support. Consumer advocates believe there is a need for ongoing support so that the newly insured retain their coverage, navigate their way effectively through the health care system, and engage in wellness and prevention activities. As many states prepare to enroll millions of low-income uninsured Americans, the experience of Community Health Workers (CHWs) in Massachusetts can inform outreach and enrollment efforts across the country.
The impact of prior authorization on buprenorphine dose, relapse rates, and cost for Massachusetts Medicaid beneficiaries with opioid dependence
OBJECTIVE: To assess the impact of a 2008 dose-based prior authorization policy for Massachusetts Medicaid beneficiaries using buprenorphine + naloxone for opioid addiction treatment. Doses higher than 16 mg required progressively more frequent authorizations.
DATA SOURCES: Mediciaid claims for 2007 and 2008 linked with Department of Public Health (DPH) service records.
STUDY DESIGN: We conducted time series for all buprenorphine users and a longitudinal cohort analysis of 2,049 individuals who began buprenorphine treatment in 2007. Outcome measures included use of relapse-related services, health care expenditures per person, and buprenorphine expenditures.
DATA COLLECTION/EXTRACTION METHODS: We used ICD-9 codes and National Drug Codes to identify individuals with opioid dependence who filled prescriptions for buprenorphine. Medicaid and DPH data were linked with individual identifiers.
PRINCIPAL FINDINGS: Individuals using doses > 24 mg decreased from 16.5 to 4.1 percent. Relapses increased temporarily for some users but returned to previous levels within 3 months. Buprenorphine expenditures decreased but total expenditures did not change significantly.
CONCLUSION: Prior authorization policies strategically targeted by dose level appear to successfully reduce use of higher than recommended buprenorphine doses. Savings from these policies are modest and may be accompanied by brief increases in relapse rates. Lower doses may decrease diversion of buprenorphine.
Variation in long-term antipsychotic polypharmacy and high-dose prescribing across physicians and hospitals
OBJECTIVES: This study had two aims: to measure the prevalence of long-term prescribing of high doses of antipsychotics and antipsychotic polypharmacy in a large Canadian province and to estimate the relative contributions of patient-, physician-, and hospital-level factors.
METHODS: Government hospital discharge, physician, and pharmaceutical claims data were linked to identify individuals with schizophrenia who in 2004 had antipsychotics available to them for at least 11 months. Individuals on a high dose throughout that period, as well as individuals on multiple concurrent antipsychotics (polypharmacy), were identified. Logistic and generalized linear mixed models using patient-, physician-, and hospital-level predictors were estimated.
RESULTS: Among the 12,150 individuals identified, 11.9% were on a high dose and 10.4% on antipsychotic polypharmacy continually, with 3.7% in both groups. After adjustment for potential confounders, analyses showed that systematic propensity for physicians to prescribe high doses accounted for 10.9% of the remaining unexplained variance, and physicians as a group who prescribed high doses across a hospital or psychiatry department accounted for 3.0%. For antipsychotic polypharmacy the corresponding percentages were 9.7% and 6.2%. Even after adjustment, the variation in high-dose prescribing and antipsychotic polypharmacy remained substantial.
CONCLUSIONS: Long-term high-dose and antipsychotic polypharmacy prescribing appeared partly driven by some physicians' and some hospitals' propensities to prescribe in this way independently of patient characteristics. Given the weight of the evidence against high-dose prescribing and antipsychotic polypharmacy, measures addressed to physicians and hospitals most likely to prescribe high doses, antipsychotic polypharmacy, or both should be considered.
OBJECTIVE: Despite the large number of Latinos living in the United States, little research has evaluated the effectiveness of different vocational rehabilitation programs for individuals with severe mental illness in this rapidly growing minority population. This article presents a secondary analysis of a randomized, controlled trial comparing supported employment with 2 other vocational rehabilitation programs in 3 ethnic/racial groups of participants with severe mental illness: Latinos, non-Latino African Americans, and non-Latino Whites.
METHOD: The data were drawn from a previously published randomized, controlled trial comparing supported employment with standard vocational rehabilitation services and a psychosocial clubhouse program in persons with severe mental illness (Mueser et al., 2004), including 64 Latinos, 91 non-Latino African Americans, and 43 non-Latino Whites. Comparisons were made between the 3 groups at baseline on demographic characteristics, clinical and psychosocial functioning, and quality of life. Within each ethnic/racial group, competitive employment and all paid employment outcomes were compared between the 3 vocational rehabilitation programs over the 2-year study period.
RESULTS: At baseline, the Latino participants had lower levels of education and disability income, were less likely to have worked competitively over the previous 5 years, had more severe symptoms, and worse psychosocial functioning than the non-Latino African American or non-Latino White participants. Latinos randomized to supported employment had better competitive and all-paid work outcomes than those assigned to either standard services or the psychosocial clubhouse program, similar to the non-Latino consumers. Rates of competitive work for consumers in supported employment were comparable across all 3 racial/ethnic groups.
DISCUSSION: Supported employment is effective at improving competitive work in Latinos with severe mental illness. Efforts should be made to increase access to supported employment in the growing population of Latinos with severe mental illness.
Policy interventions that attempt to influence patient care can be hard to implement and their desired outcomes can be slow to achieve. The efforts of the Centers for Medicare and Medicaid Services (CMS) to reduce preventable infections by withholding payment for additional expenses related to catheter-associated urinary tract infections (CAUTI) illustrate this challenge clearly.