A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Systematic literature review of the impact of psychiatric pharmacists.

Introduction: Pharmacists focusing on psychotropic medication management and practicing across a wide variety of healthcare settings have significantly improved patient-level outcomes. The Systematic Literature Review Committee of the American Association of Psychiatric Pharmacists was tasked with compiling a comprehensive database of primary literature highlighting the impact of psychiatric pharmacists on patient-level outcomes. Methods: A systematic search of literature published from January 1, 1961, to December 31, 2022, was conducted using PubMed and search terms based on a prior American Association of Psychiatric Pharmacists literature review. Publications describing patient-level outcome results associated with pharmacist provision of care in psychiatric/neurologic settings and/or in relation to psychotropic medications were included. The search excluded articles for which there was no pharmacist intervention, no psychiatric disorder treatment, no clinical outcomes, no original research, no access to full text, and/or no English-language version. Results: A total of 4270 articles were reviewed via PubMed, with 4072 articles excluded based on title, abstract, and/or full text in the initial pass and 208 articles selected for inclusion. A secondary full-text review excluded 11 additional articles, and 5 excluded articles were ultimately included based on a secondary review, for a final total of 202 articles meeting the inclusion criteria. A comprehensive database of these articles was compiled, including details on their study designs and outcomes. Discussion: The articles included in the final database had a wide range of heterogeneity. While the overall impact of psychiatric pharmacists was positive, the study variability highlights the need for future publications to have more consistent, standardized outcomes with stronger study designs.

Inequalities in life expectancy and cardiometabolic disease mortality across and within high-income countries.

Cardiometabolic disease is a leading cause of death and plays a key role in recent life expectancy trends worldwide. We highlight inequalities in cardiometabolic disease mortality across sex, race/ethnicity, geographic region, and urbanicity within the United States, as well as across high-income countries.

Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Emotional responses in archival work.

Building on previous work investigating the impact of exposure to (a) records with traumatic potentialities and (b) interactions with donors and community researchers whose suffering is documented in the archives, this study sought to better understand emotional aspects of archival work. Using a diary research methodology, 15 archivists engaged in diary keeping for approximately four months. What emerged was a broad set of events and experiences that triggered a wide range of emotional responses arising from archival work. This included: pre-existing emotional states and characterological traits; emotional exchanges in the workplace with colleagues and others; emotional demands of the work (including emotion work and emotional labour); team and leader interactions arising from group tasks and leader behaviour; and organizational policies, climate, resources and demands. This broader set of interactional factors forms the foundation on which traumatic and other troubling events are encountered. Future research must consider the nature of archival organizations and interactions within them that contribute to the overall working experience. In addition, archival organizations need to take responsibility for creating a culture that demonstrates respect and appreciation for workers, acknowledges the interpersonal challenges of the work, and provides supports for archivists who are shouldering the challenges.

Life Course Patterns of Prescription Drug Use in the United States.

Prescription drug use has reached historic highs in the United States-a trend linked to increases in medicalization, institutional factors relating to the health care and pharmaceutical industries, and population aging and growing burdens of chronic disease. Despite the high and rising prevalence of use, no estimates exist of the total number of years Americans can expect to spend taking prescription drugs over their lifetimes. This study provides the first estimates of life course patterns of prescription drug use using data from the 1996-2019 Medical Expenditure Panel Surveys, the Human Mortality Database, and the National Center for Health Statistics. Newborns in 2019 could be expected to take prescription drugs for roughly half their lives: 47.54 years for women and 36.84 years for men. The number of years individuals can expect to take five or more drugs increased substantially. Americans also experienced particularly dramatic increases in years spent taking statins, antihypertensives, and antidepressants. There are also important differences in prescription drug use by race and ethnicity: non-Hispanic Whites take the most, Hispanics take the least, and non-Hispanic Blacks fall in between these extremes. Americans are taking drugs over a wide and expanding swathe of the life course, a testament to the centrality of prescription drugs in Americans' lives today.

Utility of the Serum-Based Endoscopic Healing Index in Monitoring Therapeutic Response in Ulcerative Colitis.

INTRODUCTION: Convenient and objective noninvasive tools to monitor therapy response in patients with ulcerative colitis (UC) are needed. This study aimed to evaluate the performance of the Endoscopic Healing Index [EHI], a serum test originally developed to monitor mucosal inflammation in Crohn's disease, in patients with UC. METHODS: Serum samples paired with endoscopic data from consecutive adult patients with UC initiating advanced therapy for active disease (Mayo Endoscopic Subscore [MES] > 1) were analyzed. EHI values were compared between groups showing endoscopic improvement, remission, and nonresponse, defined, respectively, as MES of ≤1, 0 and >1. We also assessed the association of EHI with longitudinal changes of MES and compared its performance with that of fecal calprotectin (FC) and C-reactive protein. RESULTS: A total of 127 patients provided 303 samples. Median EHI increased significantly with increasing MES score ( P < 0.001). Median EHI was significantly lower in patients with endoscopic remission or improvement compared with patients with no response ( P < 0.001, P < 0.001, respectively). A 10-point decrease in EHI was associated with 89% higher odds of 1-point decrease in MES ( P < 0.001). EHI detected MES 0-1 with an area under the receiver operating curve of 77.8%, which was comparable with that of FC and C-reactive protein (85.0% [ P = 0.076] and 70.6% [ P = 0.055], respectively). DISCUSSION: EHI values are significantly responsive to changes in mucosal inflammation, also in patients with UC, and can confirm and/or rule out mucosal inflammation with an almost similar accuracy to that of FC.

A Review of Existing and New Treatments for the Management of Hand Eczema.

Hand eczema is a chronic condition that affects an estimated 14.5% of the general population. It has severe quality of life ramifications in those that struggle with it, including days missed from work or school, productivity loss and impaired work functioning. For years, the standard of care included topical moisturizing creams, topical steroids and more recently systemic agents. As new therapeutic targets emerge and recent advances are being developed, it is now more possible than ever that hand eczema can be managed via the underlying mechanisms. A review of the literature was conducted to identify current treatment options for hand eczema and chronic hand eczema. The terms 'hand eczema', 'hand dermatitis' were used to search PubMed, CENTRAL and Embase. To identify new therapies still undergoing investigation, we used the terms 'hand eczema', 'hand dermatitis', 'atopic dermatitis', and 'vesicular eczema of hands and/or feet' to search Clinicaltrials.gov for all studies until December 2022. There were 56 ongoing clinical trials identified for pharmacological treatments for hand eczema on Clinicaltrials.gov from 2000 - 2022, with 16 that are new or ongoing. These included studies for dupilumab, ruxolitinib, delgocitinib (LEO124249), gusacitinib (ASN002), AFX 5931, and roflumilast (ARQ-252). Two major classes of drugs emerging for the treatment of hand eczema include IL-4/IL-13 inhibitors and JAK inhibitors. With the increase in efficacy seen with these new drugs, we are also noting improved adverse effect profiles, making them attractive options to add to a clinician's management toolbox for patients with hand eczema.

Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.

Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.

The association between immigration status and the development of type 2 diabetes in women with a prior diagnosis of gestational diabetes: A population-based study.

AIMS: The aim of this study was to examine the influence of immigration status and region of origin on the risk of type 2 diabetes in women with prior gestational diabetes (GDM). METHODS: This retrospective population-based cohort study included women with gestational diabetes (GDM) aged 16 to 50 years in Ontario, Canada, who gave birth between 2006 and 2014. We compared the incidence of type 2 diabetes after delivery between long-term residents and immigrants-overall, by time since immigration and by region of-using Cox regression adjusted for age, year, neighbourhood income, rurality, infant birth weight and presence of hypertensive disorders of pregnancy (HDP). RESULTS: Among 38,515 women with prior GDM (42% immigrants), immigrants had a significantly higher risk of type 2 diabetes compared with long-term residents (adjusted hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.13-1.26), with no meaningful difference based on time since immigration. The highest adjusted relative risks of type 2 diabetes compared with long-term residents were found for immigrants from Sub-Saharan Africa (HR 1.63, 95% CI 1.40-1.90), Latin America/Caribbean (HR 1.44, 95% CI 1.28-1.62) and South Asia (HR 1.34, 95% CI 1.25-1.44). CONCLUSIONS: Immigration is associated with a significantly higher risk of type 2 diabetes after GDM, particularly for women from certain low- and middle-income countries. Diabetes prevention strategies will need to consider the unique needs of immigrants from these regions.

Exploring the Quality of Narrative Feedback Provided to Residents During Ambulatory Patient Care in Medicine and Surgery.

OBJECTIVES: The transition to competency-based medical education (CBME) has increased the volume of residents' assessment data; however, the quality of the narrative feedback is yet to be used as feedback-on-feedback for faculty. Our objectives were (1) to explore and compare the quality and content of narrative feedback provided to residents in medicine and surgery during ambulatory patient care and (2) to use the Deliberately Developmental Organization framework to identify strengths, weaknesses, and opportunities to improve quality of feedback within CBME. METHODS: We conducted a mixed convergent methods study with residents from the Departments of Surgery (DoS; n = 7) and Medicine (DoM; n = 9) at Queen's University. We used thematic analysis and the Quality of Assessment for Learning (QuAL) tool to analyze the content and quality of narrative feedback documented in entrustable professional activities (EPAs) assessments for ambulatory care. We also examined the association between the basis of assessment, time to provide feedback, and the quality of narrative feedback. RESULTS: Forty-one EPA assessments were included in the analysis. Three major themes arose from thematic analysis: Communication, Diagnostics/Management, and Next Steps. Quality of the narrative feedback varied; 46% had sufficient evidence about residents' performance; 39% provided a suggestion for improvement; and 11% provided a connection between the suggestion and the evidence. There were significant differences between DoM and DoS in quality of feedback scores for evidence (2.1 [1.3] vs. 1.3 [1.1]; p < 0.01) and connection (0.4 [0.5] vs. 0.1 [0.3]; p = 0.04) domains of the QuAL tool. Feedback quality was not associated with the basis of assessment or time taken to provide feedback. CONCLUSION: The quality of the narrative feedback provided to residents during ambulatory patient care was variable with the greatest gap in providing connections between suggestions and evidence about residents' performance. There is a need for ongoing faculty development to improve the quality of narrative feedback provided to residents.

Psychomotor and visual skills underlying position specialization in 1352 elite youth baseball players.

Baseball is an international sport with participation from tens of thousands of people worldwide. In the United States, the Prospect Development Pipeline (PDP) is a collaborative effort between Major League Baseball and USA Baseball to establish a developmental pipeline leading to the professional draft. Players participating in the PDP undergo comprehensive evaluations that measure athletic performance, speed-of-processing, visual function, and on-field talent. The present study evaluated data from 1352 elite junior male PDP participants (aged 14 to 21) who signed informed consent, collected between 2017 and 2020, to identify latent abilities and their association with player specialization. Data were first subjected to Exploratory Factor Analysis (EFA) to reduce the 22 measured variables to a smaller set of latent abilities. The resulting factors were evaluated using multiple linear regression to predict each factor using age, height, weight, and position. EFA revealed a combination of physical and psychomotor skills accounting for 52% of the overall variance that grouped into four abilities: grip strength, functional vision, explosiveness, and rapid decision-making. Regression analyses demonstrated that these skills are associated with position assignments, controlling for age, weight, and height, and revealed that outfielders are the most explosive, infielders perform best on psychomotor measures, and catchers perform best on functional vision tests (ps < 0.001). These findings indicate skills that contribute to player specialization, providing new information about the developmental trajectory of junior elite baseball athletes that can be used for scouting and player development.

The Relationship Between Multimorbidity and Types of Chronic Diseases and Self-Rated Memory.

This study explores the impact of multimorbidity and types of chronic diseases on self-rated memory in older adults in the United States. Data were drawn from the 2011 wave of the National Health and Aging Trends Study (NHATS, N = 6,481). Logistic regressions were used to examine the associations between multimorbidity and types of chronic diseases and fair/poor self-rated memory. Compared to respondents with no or one chronic disease, respondents with multimorbidity showed 35% higher odds of reporting fair/poor self-rated memory. Also, stroke, osteoporosis, and arthritis were identified as increasing the odds of reporting fair/poor self-rated memory by 41%, 20%, and 30%, respectively. Demonstrating the importance of both multimorbidity and types of chronic diseases in self-reporting of memory, our findings suggest the need to educate older adults with multimorbidity and certain types of diseases regarding negative self-rated memory and its consequences.

Smoking and the widening inequality in life expectancy between metropolitan and nonmetropolitan areas of the United States.

Background: Geographic inequality in US mortality has increased rapidly over the last 25 years, particularly between metropolitan and nonmetropolitan areas. These gaps are sizeable and rival life expectancy differences between the US and other high-income countries. This study determines the contribution of smoking, a key contributor to premature mortality in the US, to geographic inequality in mortality over the past quarter century. Methods: We used death certificate and census data covering the entire US population aged 50+ between Jan 1, 1990 and Dec 31, 2019. We categorized counties into 40 geographic areas cross-classified by region and metropolitan category. We estimated life expectancy at age 50 and the index of dissimilarity for mortality, a measure of inequality in mortality, with and without smoking for these areas in 1990-1992 and 2017-2019. We estimated the changes in life expectancy levels and percent change in inequality in mortality due to smoking between these periods. Results: We find that the gap in life expectany between metros and nonmetros increased by 2.17 years for men and 2.77 years for women. Changes in smoking-related deaths are responsible for 19% and 22% of those increases, respectively. Among the 40 geographic areas, increases in life expectancy driven by changes in smoking ranged from 0.91 to 2.34 years for men while, for women, smoking-related changes ranged from a 0.61-year decline to a 0.45-year improvement. The most favorable trends in years of life lost to smoking tended to be concentrated in large central metros in the South and Midwest, while the least favorable trends occurred in nonmetros in these same regions. Smoking contributed to increases in mortality inequality for men aged 70+, with the contribution ranging from 8 to 24%, and for women aged 50-84, ranging from 14 to 44%. Conclusions: Mortality attributable to smoking is declining fastest in large cities and coastal areas and more slowly in nonmetropolitan areas of the US. Increasing geographic inequalities in mortality are partly due to these geographic divergences in smoking patterns over the past several decades. Policies addressing smoking in non-metropolitan areas may reduce geographic inequality in mortality and contribute to future gains in life expectancy.

Transitioning to virtual ambulatory care during the COVID-19 pandemic: a qualitative study of faculty and resident physician perspectives.

BACKGROUND: The COVID-19 pandemic resulted in a rapid shift from in-person to virtual care delivery for many medical specialties across Canada. The purpose of this study was to explore the lived experiences of resident physicians and faculty related to teaching, learning and assessment during ambulatory virtual care encounters within the competency-based medical education model. METHODS: In this qualitative phenomenological study, we recruited resident physicians (postgraduate year [PGY] 1-5 trainees) and faculty from the Departments of Surgery and Medicine at Queen's University, Ontario, via purposive sampling. Participants were not required to have exposure to virtual care. Interviews were conducted from September 2020 to March 2021 by 1 researcher, and 2 researchers conducted focus groups via Zoom to explore participants' experiences with the transition to virtual care. These were audio-recorded and transcribed verbatim; qualitative data were analyzed thematically. RESULTS: There were 18 male and 19 female participants; 20 were resident physicians and 17 were faculty; 19 were from the Department of Surgery and 18 from the Department of Medicine. All faculty participants had participated in virtual care during ambulatory care; 2 PGY-1 residents in surgery had not actively participated in virtual care, although they had participated in clinics where faculty were using virtual care. The mean age of faculty participants was 38 (standard deviation [SD] 8.6) years, and the mean age of resident physicians was 29 (SD 5.4) years. Overall, 28 interviews and 4 focus groups (range 2-3 participants per group) were conducted, and 4 themes emerged: teaching and learning, assessment, logistical considerations, and suggestions. Barriers to teaching included the lack of direct observations and teaching time, and barriers to assessment included an absence of specific Entrustable Professional Activities (EPAs) and feedback focused on virtual care-related competencies. Logistical challenges included lack of technological infrastructure, insufficient private office space and administrative burdens. Both resident physicians and faculty did not foresee virtual care limiting resident physicians' ability to progress within competency-based medical education. Benefits of virtual care included increased accessibility to patients for follow-up visits, for disclosing patients' results and for out-of-town visits. Suggestions included faculty development, improved access to technology and space, educational guidelines for conducting virtual care encounters, and development of virtual care-specific competencies and EPAs. INTERPRETATION: In the postgraduate program we studied, virtual care imposed substantial barriers on teaching, learning and assessment during the first year of the COVID-19 pandemic. Adapting to new circumstances such as virtual care with suggestions from resident physicians and faculty may help to ensure the continuity of postgraduate medical education throughout the COVID-19 pandemic.

Rapid, scalable assessment of SARS-CoV-2 cellular immunity by whole-blood PCR.

Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations.

Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4.

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

Concomitant therapy of surgical shave excision and intralesional injections for ear keloids: Early results from a retrospective cohort study.

Introduction: Keloids are hypertrophic scars that commonly arise in the ear region. The authors' objectives were to (1) evaluate effectiveness of surgical shave excision followed by intralesional triamcinolone acetonide and onabotulinumtoxinA injections; and (2) evaluate safety and patient satisfaction. Methods and Materials: This study was a retrospective chart review of patients who received treatment of extralesional surgical shave excision followed by intralesional triamcinolone acetonide and onabotulinumtoxinA injections to treat ear keloids at a single outpatient dermatology clinic. A prospective patient questionnaire was administered to the same patient population to collect recurrence and patient satisfaction. Results: A total of 45 patients were included, consisting of 84.4% females (n = 38) and 15.6% males (n = 7) with a mean age of 25.5 years. Through retrospective chart review, early recurrence was seen in 6.7% of patients (n = 3), and via the prospective patient questionnaire, 11.1% of patients noted early keloid recurrence (n = 5). Of the patients who expressed their level of satisfaction in-clinic, 96.0% (n = 24) reported being satisfied or very satisfied and 4.0% (n = 1) were dissatisfied. Satisfaction was also assessed through the prospective patient questionnaire; of those who consented to the questionnaire, 100.0% (n = 24) were satisfied or very satisfied. Only 20.0% (n = 9) of all patients reported experiencing side effects, consisting of pruritus (11.1%; n = 5), tenderness (4.4%; n = 2), pain (2.2%; n = 1), and mild atrophy (2.2%; n = 1). Conclusion: Extralesional surgical shave excision followed by intralesional triamcinolone acetonide and onabotulinumtoxinA injections may represent a promising treatment option for ear keloids.Evidence Level: 3 retrospective cohort study. Lay Summary: Keloids are a type of raised scar, which can be painful and itchy for patients. Keloids can occur on various part of the body, including on the ear. They are challenging to treat and tend to come back. There are many treatment options, however, there is not one universal best treatment for keloids on the ear. We hoped to discover if shave excision followed by intralesional triamcinolone acetonide and onabotulinumtoxinA injections is effective at treating keloids on the ear. In order to answer this we completed a chart review of clinic patients, who have already completed the following combination treatment for keloids on the ear. The keloids were treated first by physically removing the bulk of the keloid with a scalpel, which is called shave excision. After the removal, triamcinolone acetonide and onabotulinumtoxinA were injected directly into the keloid. The rate of patient satisfaction and the rate of the keloid returning were collected during in-clinic visits and an optional post-clinic patient questionnaire. The treatment effectiveness and side effects experienced were reported during in-clinic visits. This indicated that with the low rate of side effects, high patient satisfaction, and low rate of keloid return, this treatment combination should be considered as an option for keloids on the ear. However, since this review was completed at one clinic with a small population of patients, it is not fully known if this treatment combination will work for all patients.