Citations

Abstract The treatment of diabetes mellitus type 2 (DM2) is becoming more complex as new medications are approved. Primary care providers must maintain their medical knowledge on emerging medications for best patient care. This review simplifies the non-insulin treatments of diabetes with an emphasis on the cardio-renal protectants, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1).

AbstractObjectiveThis systematic review updates the evidence for association between oral health characteristics and frailty status, identifying gaps in translational dental research and application of frailty assessment into clinical practice.BackgroundClinicians have little guidance on stage‐appropriate dental treatment for medically complex older adults. Oral health characteristics have been associated with frailty status, determined through validated assessment tools representing a concise measure of health. Translation of frailty assessment into dental practice has not been the focus of previous reviews.MethodsUtilising the PRISMA framework for systematic reviews, a comprehensive database search identified articles describing the association of interest. Those included were cross‐sectional or longitudinal, in English, included participants aged 50 years or older, used validated frailty assessments and measured clinically relevant oral health outcomes. From 835 screened articles, 26 full‐text articles were eligible for quality appraisal and synthesis.ResultsFrailty prevalence ranged from 8.5% to 66.0%. Most studies utilised the Fried frailty criteria. Qualitative synthesis of 17 cross‐sectional and nine longitudinal studies demonstrated significant covariate‐adjusted association between frailty status and number of teeth, chewing ability, prosthetic characteristics, dental caries, periodontitis, dental utilisation and oral health‐related quality of life factors. Variability in findings reflected study sample diversity based on country of study origin, age at recruitment, sample size, frailty assessment type, use of clinical versus self‐reported outcome measures and differences in statistical analysis.ConclusionDespite robust evidence of association with oral health characteristics, frailty assessment has yet to be sufficiently applied to translational dental research and clinical practice.

INTRODUCTION: Studies suggest 8%-28% of ischemic strokes present as wake-up strokes (WUS). The unknown time of symptom onset precludes these patients from approved treatments for acute ischemic stroke, but a substantial proportion of patients may be deemed candidates for treatment if other factors are considered. The aim of this study was to identify characteristics associated with clinical outcomes of WUS patients. METHODS: We retrospectively reviewed the medical record of patients with ischemic stroke admitted to a large academic medical center between January 2011 and May 2012. We identified patients with stroke symptoms upon awakening or those who were found with stroke symptoms with an unknown time of onset. Baseline demographics, stroke mechanism, presenting NIHSS, Alberta Stroke Program Early Computed Tomography Score (ASPECTS), and modified Rankin Scale (mRS) scores on discharge and at 3-month follow-up were obtained. A good outcome was defined as mRS 0-2. RESULTS: WUS patients comprised 22% (162/731) of all patients with ischemic stroke at our institution during this time period. Median age was 74 years (range 15-100), median presenting NIHSS was 5 (range 0-28), and median initial ASPECTS 10 (range 0-10). A cardioembolic mechanism was identified in 68 patients (42%). Predictors of good outcome at hospital discharge were lower initial NIHSS (3.5 versus 12.0, p<0.0001) and higher ASPECTS (9.8 versus 8.1, p=0.0002). The predictors of good outcomes at 3 months were younger age (69.1 versus 75.8, p=0.009), lower initial NIHSS (5.0 versus 12.6, p<0.0001), and higher ASPECTS (9.5 versus 8.1, p=0.0006). One hundred and eleven patients (68.5%) had initial ASPECTS of 10. Of those, 19 had NIHSS≥10 and 7 were treated with acute recanalization therapies. Four of the 7 treated patients had good outcomes, and 2 of the 12 untreated patients had good outcomes. CONCLUSIONS: Few patients with strokes of unknown onset and severe deficits have good outcomes without acute stroke treatment. Patients with NIHSS≥10 and ASPECTS 10 may be candidates for acute recanalization therapy.

Abstract Clinical practice guidelines recommend that individuals with HC MBL are evaluated annually for evidence of progression as it has been shown that they progress to develop CLL requiring therapy at a rate of 1-5%/year. Next-generation sequencing identified 59 genes recurrently mutated in CLL, and we previously showed that the tumor mutational load (TML), i.e., the total number of these genes mutated, is associated with a shorter time to first treatment (TTT) among 112 HC MBLs independent of the CLL international prognostic index (CLL-IPI), an established prognostic score. Herein, we continue to support our finding in additional HC MBLs and report the pooled results across the two cohorts. From the Mayo Clinic CLL Resource, we sequenced a total 167 HC MBL (112 from the initial round and 55 from additional sequencing). We extracted DNA from CD5+/CD19+ B-cells and sequenced the coding regions of 59 driver genes. Somatic mutations were called using MuTect2 in tumor-only mode. Germline variants were eliminated based on minor allele frequencies &gt;0.01% and by those identified in public databases, unless present in known CLL mutation hotspots. After filtering, we computed the TML based on the number of genes with high impact (nonsense, frameshift and splicing) and hotspot mutations. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for sex and CLL-IPI. Stratified analyses were conducted by low/intermediate risk and high/very high CLL-IPI. Of the 167 HC MBL, low risk CLL-IPI comprised 60%, intermediate risk 28%, high risk 12%; and none were very-high risk. The most commonly mutated genes were SF3B1 (11%), NOTCH1 (9%), TP53 (7%), BIRC3 (7%), and MYD88 (6%); and 52 (31%) individuals had mutations in at least one gene. The median follow-up was 4.4 years, and 26 of the 167 individuals progressed to CLL requiring therapy. HC MBL with ≥2 mutated genes had a 28% 5-year risk of needing therapy compared to 6% among those with no mutated genes. Similar to our initial finding (HR=1.53, CI:1.12-2.07; P=0.007), we found a shorter TTT in the additional HC MBLs (HR=4.63, CI:1.57-13.7, P=0.006), and in the pooled cohort (HR=1.72; CI:1.29-2.28, P=0.0002). When we stratified by CLL-IPI risk, TML remained associated with TTT among individuals with low/intermediate CLL-IPI risk in the additional HC MBLs (HR=3.52, CI:1.11-11.2, P=0.03) and in the pooled cohort (HR=2.25, CI:1.34-3.77, P=0.002). A non-significant 2.8 fold association was observed with high risk CLL-IPI in the pooled cohort. In conclusion, the TML along with the CLL-IPI provide clinicians with a more accurate prognostic information regarding disease progression requiring therapy, especially for those MBLs with low to intermediate risk based on CLL-IPI. If validated, these findings may modify current practice guidelines for individuals with HC MBL. Citation Format: Geffen Kleinstern, Cecilia Bonolo de Campos, Nicholas J. Boddicker, Daniel R. O'Brien, Shulan Tian, Chantel Barney, Kari G. Rabe, Cristine Allmer, Laura Bruins, Aaron D. Norman, Timothy G. Call, Sameer A. Parikh, Jose F. Leis, Wei Ding, Huihuang Yan, James R. Cerhan, Neil E. Kay, Celine Vachon, Esteban Braggio, Susan L. Slager. Tumor mutational load derived from recurrently mutated genes in chronic lymphocytic leukemia (CLL) predicts time-to-first treatment in high-count monoclonal B-cell lymphocytosis (HC MBL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 884.

Abstract Chronic lymphocytic leukemia (CLL) is a neoplastic disease of mature B-cells with a highly heterogeneous clinical course. While European ancestry (EA) populations present an increased incidence of CLL, African ancestry (AA) populations have a younger median age of onset, higher frequency of adverse prognostic factors, and inferior clinical outcomes. Despite the considerable effort to characterize the genetic landscape of CLL, AA are overwhelmingly underrepresented. Our hypothesis is that the clinical differences observed between AA and EA populations are, in part, explained by underlying genetic features. To address this imbalance, we identified 90 AA patients diagnosed with CLL, 64% of which were untreated at sample collection. RNA and DNA were extracted from CD5+/CD19+ clonal B-cells. We performed mRNA-seq and targeted sequencing in 59 recurrently mutated somatic CLL driver genes. Differentially expressed genes were identified using edgeR. Data was compared to our previously analyzed EA CLL cohort (N=445). The median age at diagnosis was 59 years for AA and 66 for EA and 74% of AA and 50% of EA had unmutated IGHV (u-IGHV) status. When evaluating the entire AA and EA cohorts, there was a significant increased frequency of mutations in TP53, SF3B1, and NFKBIE, identified in 29%, 24%, and 20% of AA CLLs, compared to 5%, 9%, and 9%, respectively, in EA CLLs (p&lt;0.01). When exclusively evaluating the untreated and u-IGHV cases, AA CLLs showed greater proportion of TP53 (30% vs 12%; p=0.0145), NFKBIE (30% vs 15%; p=0.0492), BIRC3 (21% vs 10%; p=0.0697), and KRAS (15% vs 7%; p=0.1683). Furthermore, there was an increase in mutations targeting relevant molecular pathways, such as NF-κB (42% vs 15%) and MAPK (18% vs 8%). Upregulation MAPK pathway was also confirmed by mRNA-seq analysis in the AA u-IGHV CLLs. Because of the high prevalence of TP53 mutations in the AA cohort, we further evaluated differential gene expression in the DNA Damage/Telomere Stress-Induced Senescence pathway. AA CLLs presented a significant downregulation of multiple genes associated with genome stability and cellular DNA damage response - DDR (including TP53 and ATM), double strand break repair (H2AFX and RAD50), telomere maintenance (POT1 and ACD), and cell cycle regulation (RB1, CCNA1, and CCNE2) (FDR&lt;0.05). DDR is responsible for DNA repair or induction of apoptosis, with its deficiency resulting in the accumulation of chromosomal aberrations, negatively impacting clinical outcome in CLL. Disparities in cancer are influenced by numerous factors that affect disease risk, screening and diagnosis, access to treatment, and survival. We identified an increased number of genomic alterations in the AA CLL cohort, primarily inducing activation of NF-κB and MAPK pathways and DDR impairment, with the increased frequency of mutations, notably in TP53 and BIRC3, expected to negatively impact prognosis. Citation Format: Cecilia Bonolo de Campos, Daniel R. O'Brien, Chantal E. McCabe, Huihuang Yan, Geffen Kleinstern, Zhiquan Wang, Laura A. Bruins, Cristine Allmer, Nicholas J. Boddicker, Charla R. Secreto, Aaron D. Norman, Shulan Tian, Kari G. Rabe, Timothy G. Call, Sameer A. Parikh, Jose F. Leis, Wei Ding, Richard Furman, J Brice Weinberg, James R. Cerhan, Celine M. Vachon, Neil E. Kay, Susan L. Slager, Esteban Braggio. Characterization of underlying genomic features among African ancestry populations diagnosed with chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2209.

Red Man Syndrome is a term used for an adverse event attributed to vancomycin infusion. Based on the presentation within white patients, the term is imprecise at best and can lead to suboptimal classification and management. Recent calls have advocated for the discontinuation of the use of this terminology. Pharmacists should take the lead in advocating for this change.

Abstract Background As a major public health crisis, the novel coronavirus disease 2019 (COVID-19) pandemic demonstrates the urgent need for safe, effective, and evidence-based implementations of digital health. The urgency stems from the frequent tendency to focus attention on seemingly high promising digital health interventions despite being poorly validated in times of crisis. Aim In this paper, we describe a joint call for action to use and leverage evidence-based health informatics as the foundation for the COVID-19 response and public health interventions. Tangible examples are provided for how the working groups and special interest groups of the International Medical Informatics Association (IMIA) are helping to build an evidence-based response to this crisis. Methods Leaders of working and special interest groups of the IMIA, a total of 26 groups, were contacted via e-mail to provide a summary of the scientific-based efforts taken to combat COVID-19 pandemic and participate in the discussion toward the creation of this manuscript. A total of 13 groups participated in this manuscript. Results Various efforts were exerted by members of IMIA including (1) developing evidence-based guidelines for the design and deployment of digital health solutions during COVID-19; (2) surveying clinical informaticians internationally about key digital solutions deployed to combat COVID-19 and the challenges faced when implementing and using them; and (3) offering necessary resources for clinicians about the use of digital tools in clinical practice, education, and research during COVID-19. Discussion Rigor and evidence need to be taken into consideration when designing, implementing, and using digital tools to combat COVID-19 to avoid delays and unforeseen negative consequences. It is paramount to employ a multidisciplinary approach for the development and implementation of digital health tools that have been rapidly deployed in response to the pandemic bearing in mind human factors, ethics, data privacy, and the diversity of context at the local, national, and international levels. The training and capacity building of front-line workers is crucial and must be linked to a clear strategy for evaluation of ongoing experiences.

We are grateful to all of our commentators. They have provided a wide range of valuable perspectives and insights from many fields, revealing a broad interest in the subject matter. Nearly all the commentaries have helped to affirm, refine, expand, amplify, deepen, interpret, elaborate, or apply the messages in the target article. Some have offered critiques and suggestions that help us address certain issues in greater detail, including several points concerning industrialized farming and the wildlife trade. Overall, there is great awareness and strong consensus among commentators that any solution for preventing future pandemics and other related health crises must take into account not only what is best for humans but also what is best for nonhumans and the environment, given the profound interconnectedness of all life.