Storylines of family medicine III: core principles-primary care, systems and family.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'III: core principles-primary care, systems, and family', authors address the following themes: 'Continuity of care-building therapeutic relationships over time', 'Comprehensiveness-combining breadth and depth of scope', 'Coordination of care-managing multiple realities', 'Access to care-intersectional, systemic, and personal', 'Systems theory-a core value in patient-centered care', 'Family-oriented practice-supporting patients' health and well-being', 'Family physician as family member' and 'Family in the exam room'. May readers develop new understandings from these essays.

Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 µg once daily (QD) for week 1 and 500 µg three times weekly (TIW) thereafter (250 µg/500 µg) or (2) 500 µg QD for week 1 and 1000 µg TIW thereafter (500 µg/1000 µg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 µg/500 µg dose and 13 at 500 µg/1000 µg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 µg/500 µg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 µg/1000 µg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.

The learning community faculty experience: how longitudinal relationships with learners enhance work meaning.

INTRODUCTION: Work meaning has gained attention as an important contributor to physician job engagement and well-being but little is known about how faculty participation in medical school learning communities might influence this phenomena. Our study goals were to determine how physician faculty members may derive meaning from serving as mentors for longitudinal learning communities of medical students, to understand how that meaning may impact other areas of their work, and relate our findings to existing literature and theoretical frameworks. METHODS: The research team conducted, recorded, transcribed, and coded 25 semi-structured telephone interviews of faculty mentors from four US medical schools with curricular learning communities. The team used an iterative interview coding process to generate final themes and relate these themes to existing literature. RESULTS: The authors identified five themes of meaning faculty derive from participation as learning community mentors: "I am a better professional," "I am more connected," "I am rejuvenated," "I am contributing," and "I am honored." A sixth theme, "I am harmed," encompassed the negative aspects of the learning community faculty experience. The authors found that their identified themes related closely to the theoretical framework for pathways to meaningful work proposed by Rosso et al. DISCUSSION: The alignment of the themes we identified on the experience of learning community faculty to existing literature on work meaning corroborates the theoretical framework and deepens understanding of beneficial and harmful learning community effects on faculty. As learning communities become increasingly common within medical schools, this understanding may be important for leaders in academic medicine considering potential indirect benefits of this educational model.

A Listening Tour: Conversations about Obamacare across America's Heartland.

During my sabbatical, I rode my bike 3300 miles from Washington, DC, to Seattle, WA, in order to engage in dialog with people along the northern tier of America's heartland. Through informal and candid conversations with >100 people, I gained insights into attitudes and opinions about the Patient Protection and Affordable Care Act (Obamacare). The comments were overwhelmingly negative. In this reflective essay, I share some of the conversations I had and the insights I gained from this remarkable journey across our beautiful country.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.

Opposition to Obamacare: A Closer Look.

Prior telephone surveys have reported two main reasons for opposition to the Affordable Care Act (ACA): distrust of government and opposition to the universal coverage mandate. The authors set out to elucidate the reasons for this opposition. This article describes how the authors used qualitative methods with semistructured interviewing as a principal investigative method to gather information from people they met while bicycling across the United States from April through July 2016. During this time, the authors conducted open-ended, semistructured conversations with people they met as they rode their bicycles from Washington, DC, to Seattle, Washington. Informants were chosen as a convenience sample. One hundred sixteen individuals participated as informants. The majority of comments were negative toward the ACA. Conversations were categorized into four themes, which included the following: (1) The ACA has increased the cost of health insurance; (2) government should not tell people what to do; (3) responsibility for ACA problems is diffuse; and (4) the ACA should not pay for other people's problems. These face-to-face conversations indicated that opposition to the ACA may be due to the fact that many Americans have experienced an increase in the cost of insurance either through increased premiums or greatly increased deductibles. They blame this increase in cost on the ACA, President Obama, the government or insurance companies, and the inclusion of "others" in insurance plans. The authors discuss how these findings can influence medical education curricula to better prepare future physicians to discuss health policy issues with patients.

How Can Physicians Educate Patients About Health Care Policy Issues?

Complicated health care policy decisions are generally made by elected officials. The officials making these complicated decisions are elected by the people, and citizens' participation in the voting process is one of the basic tenets of democracy. Voters in the United States, who are also patients in the health care system, receive enormous amounts of information throughout election cycles. This information is generally delivered in sound bites often intended to elicit an emotional reaction rather than simply inform. From April through July 2016, the author-an academic physician-rode a bicycle across the United States and met with people in small rural towns to ask them their understanding of the Affordable Care Act and the impact it has had on their lives. In this Commentary the author shares some of those stories, which are often informed by sound bites and misinformation. The author argues that it is the role of academic physicians to educate not only students and residents but also patients. In addition to providing information about patients' medical problems, physicians can educate them about the health care policy issues that are decided by elected officials.A doctor can help educate patients about these issues to facilitate their making informed decisions in elections. Physicians have a role and responsibility in society as a knowledgeable person to make the health care system be the best it can be for the most people.

Using standardized patients to evaluate medical students' evidence-based medicine skills.

OBJECTIVES: To analyze the effectiveness of an Evidence Based Medicine Objective Structured Clinical Examination (EBM OSCE) with standardized patients for end of third year medical students at our institution. METHODS: This was a single-center prospective cross-sectional investigation. As part of the eight-station OSCE exam, the authors developed and implemented a new 25-minute EBM OSCE station with the goal of evaluating evidence based medicine skills necessary for daily clinical encounters. The OSCE case involved a highly educated patient with a history of recurrent debilitating migraines who has brought eight specific questions regarding the use of steroids for migraine headaches. Students were provided computer stations equipped to record a log of the searches performed. RESULTS: One hundred and four third-year medical students participated in this study. The average number of search tools used by the students was 4 (SD = 2). The 104 students performed a total of 896 searches. The two most commonly used websites were uptodate.com and google.com. Sixty-nine percent (95% CI, 60% to 78%) of students were able to find a meta-analysis regarding the use of dexamethasone for the prevention of rebound migraines. Fifty-two percent of students were able to explain that patients who took dexamethasone had a moderate RR (0.68 to 0.78) of having a recurrent migraine, and 71% of students were able to explain to the standardized patient that the NNT for dexamethasone was nine. CONCLUSION: The EBM OSCE was successfully integrated into the existing eight-station OSCE and was able to assess student EBM skills.

KnowPain-50: a tool for assessing physician pain management education.

BACKGROUND: Despite a need for better physician pain management education, there are no widely accepted assessment or outcome measures to support this work. OBJECTIVE: Create a self-assessment tool to measure physician educational needs and the effectiveness of chronic pain educational programs. DESIGN: We used expert consensus to draft a 142-item survey that covered essential areas of chronic pain management. We tested the survey in 106 physicians, including 22 pain management experts and used predefined psychometric criteria to eliminate 70 items. We then eliminated 22 remaining items that did not correlate with the management of a standardized chronic pain patient by 27 academic physicians. We evaluated internal consistency using Cronbach's alpha. RESULTS: The final 50-item survey assessed physician knowledge, attitudes, and beliefs in: 1) initial pain assessment; 2) defining goals and expectations; 3) development of a treatment plan; 4) implementation of a treatment plan; 5) reassessment and management of longitudinal care; and 6) management of environmental issues. The survey demonstrated good internal consistency in all physician populations studied (alpha = 0.77-0.85). Average scores in 84 "pilot" physician users of a CME Website (135.8-138.5) were significantly lower (P < 0.01) than scores in 27 academic physicians (150.0), or 22 pain experts (177.5). CONCLUSIONS: This survey, the KnowPain-50, has good psychometric properties, correlates with clinical behaviors, and appears to distinguish between physicians with different levels of pain management expertise. It may be a useful measure of the effectiveness of physician pain management education programs.

The variable response of women with menopausal hot flashes when treated with sertraline.

OBJECTIVE: To evaluate the variable response of women when treated with a selective serotonin reuptake inhibitor (sertraline) to decrease hot flashes. DESIGN: A double-blind, placebo-controlled, crossover trial was conducted in 102 women aged 40 to 65 years who were experiencing hot flashes and not taking any hormone therapy. The original purpose of the study was to evaluate the effectiveness of sertraline for the treatment of hot flashes. After 1 week of baseline hot flash data collection, study participants were randomized to receive placebo or active drug (sertraline 50 mg) for 4 weeks. This intervention was followed by a 1-week washout and crossover to the opposite treatment for 4 weeks. The number and severity of hot flashes were measured. RESULTS: One hundred two women were enrolled in the study, and 87 completed the study. The average response was a statistically significant but clinically modest reduction in hot flash frequency and hot flash index (frequency x severity). These data on the average response have been previously published. Although the average response was modest, some women responded vigorously, others modestly, and some women actually worsened. This is a post hoc analysis of those data. Percentage of change was divided into three categories of clinical response: women with a clinically significant reduction (>or=30%, n=27), women with a nonsignificant reduction (<30% to none, n=28), and women with an increase (1%-100%, n=32). A vigorous response to sertraline for the treatment of hot flashes was related to activity level, education, and menopausal status. CONCLUSIONS: Women have markedly variable responses when treated with antidepressants for their hot flashes. We have begun to describe the characteristics of those most likely to respond to treatment with a selective serotonin reuptake inhibitor.

Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population.

OBJECTIVE: To evaluate the effectiveness of a selective serotonin reuptake inhibitor (SSRI) (sertraline) in decreasing hot flashes in a general population of women. DESIGN: A double-blind, placebo-controlled, crossover trial was conducted in a southwestern urban setting. A total of 102 women aged 40 to 65 who were experiencing hot flashes and not taking any hormone therapy were recruited. After 1 week of baseline hot flash data collection, study participants were randomized to receive placebo or active drug (sertraline 50 mg) for 4 weeks. This intervention was followed by a 1-week washout and cross over to the opposite treatment for 4 weeks. The number and severity of hot flashes were measured. RESULTS: One hundred two women were enrolled in the study. Five dropped out before providing baseline data. Of the 97 remaining, 52 were randomized to active drug first and 45 to placebo first. Ten dropped out of the study before completing all 10 weeks, leaving 46 in the active drug-first arm and 41 in the placebo-first arm. At baseline, the mean number of hot flashes reported was 45.6 per week (SD = 29.6), ranging from 2 to 148. During the sertraline phase of the study, women experienced five fewer hot flashes per week than they did on the placebo (P = 0.002). The severity of hot flashes was not significantly different; however, the hot flash score (number x average severity) was significantly improved during the sertraline phase. CONCLUSION: Sertraline reduced the number of hot flashes and improved the hot flash score relative to placebo and may be an acceptable alternative treatment for women experiencing hot flashes.

Thoughts on communication.

Living without the ability to communicate is humbling. Time spent on a sabbatical in Florence, Italy, taught me that my outgoing manner, my interactional skills, and my ability to establish rapport, all personality traits and skills that I thought would overcome my inadequacies as a communicator in Italian are not immutable. I gained some understanding of what our nonnative English-speaking patients might feel. I learned the following lessons: (1) be cautious-what appears to be a lack of interest may be a lack of understanding; (2) our perceptions of aptitude may be mistaken if based on patients' facial expressions and body language; (3) we should not adjust our words and speed of speech just because we think a patient cannot understand what we are saying; and (4) language is an amazingly powerful tool-the inability to communicate transforms us.

Biology and plasticity of CD133+ hematopoietic stem cells.

AC133 (CD133) is a highly conserved antigen expressed on hematopoietic stem cells with unknown function. In order to further characterize CD133(+) progenitor cells, we purified CD133(+) stem cells using the method of magnetic activated cell sorting (MACS) from healthy adult volunteers mobilized with granulocyte colony-stimulating growth factor (G-CSF) to a mean purity of 94%. The purified CD133(+) cells highly engrafted NOD/SCID mice. In addition, unseparated mononuclear cells or CD133(+) stem cells isolated from the bone marrow of transplanted NOD/SCID mice gave rise to engraftment of secondary recipients. Upon ex vivo culture of purified CD133(+) cells with FLT3/Flk2 ligand (FL) and interleukin-6 (IL-6), a plastic-adherent cell population could be observed after 6 weeks in culture. These adherent cells did not express CD34 or CD133 antigens on their surface, nor did they express markers for endothelial, mesenchymal, or dendritic cells. After incubation of these adherent cells with stem cell factor (SCF), non-adherent cells were observed which partially co-expressed CD133, but were negative for CD34. These nonadherent CD34(-) cells showed a high engraftment capacity in NOD/SCID mice. From our results, we conclude that CD133 might be a marker of early progenitors with a high NOD/SCID engraftment potential. The fact that CD133(+) hematopoietic progenitors can give rise to an adherent population which is CD133(-) and CD34(-) and that these cells can again give rise to a CD133(+)CD34(-) stem cell population with high NOD/SCID engraftment potential indicates the plasticity of hematopoietic precursors. CD133(+) stem cells might be useful for research and for clinical application.

Ultrastructure of the rumen ciliate Dasytricha ruminantium.

The ciliate Dasytricha ruminantium possesses cilia over the entire surface. Both the oral and somatic kineties are composed of monokinetids comprising a kinetosome, a tangential ribbon of 5 transverse microtubules, a weakly convergent bundle of 5 postciliary microtubules, a short kinetodesmal fibre, and a single microtubule homologous to T(2) of other litostomate ciliates [15]. The reversed orientation of the kineties within and around the vestibulum may be a consequence of the evolutionary migration of the vestibulum from the anterior to the posterior of the cell. The vestibulum leads to the cytostome and a cytopharynx of the rhabdos type [3]. Microtubules lining the exit canals of the posterior contractile vacuole and cytoproct are believed to originate from somatic kinetids. The ecto-endoplasmic boundary layer (eeb) is composed of two microfibrillar layers. A large extension of the eeb connects the vestibulum to the cell cortex but does not form a karyophore as seen in the closely related genus Isotricha [12].