Search

Alzheimer’s disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer’s disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides1, inflammasome signaling2 and disrupted blood brain barrier3. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer’s disease4,5. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults6,7, contributes to the inflammation and pathogenesis of Alzheimer’s disease. Here we show that the choroid plexus in Alzheimer’s disease exhibits a pro-inflammatory signature with aberrant protein accumulations, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer’s disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer’s disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer’s disease.

The spread of coronavirus disease 2019 has drastically altered the medical landscape and profoundly affected the way we conduct our vascular surgery practices. The pandemic was a time of change, not only in the way health care was provided, but also in how people in the health care systems interacted. Social media has rapidly become a crucial communication tool, combining physical distancing and digital connectedness. This article provides an overview of the use of online platforms in vascular surgery as a response of our community to the pandemic.

Key Points Question What genetic variants are associated with juvenile amyotrophic lateral sclerosis (ALS)? Findings In this family-based genetic study, exome sequencing was performed in 3 patients diagnosed with juvenile ALS and failure to thrive; this identified de novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Variants in SPTLC1 are a known cause of hereditary sensory and autonomic neuropathy, type 1A, and these data extend the phenotype associated with this gene. Meaning De novo variants in the SPTLC1 gene are associated with juvenile ALS, a fatal neurological disorder., This genetic association study identifies genetic variants associated with juvenile amyotrophic lateral sclerosis., Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures De novo variants present only in the index case and not in unaffected family members. Results Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Background: Antiplatelet therapy is a cornerstone in the management of carotid artery disease following carotid endarterectomy (CEA). There is a paucity of data regarding the effect of dual antiplatelet therapy (DAPT) on restenosis rates. Methods: A retrospective review of patients who underwent CEA from January 1, 2007 to December 31, 2013 was performed at a single center. Study groups consisted of subjects who received DAPT and those who received single antiplatelet therapy (SAPT) following CEA. Restenosis was evaluated by carotid duplex. Severity and timing of restenosis, postoperative complications, and reinterventions were compared between study groups. Results: Between January 1, 2007 and December 31, 2013, 1453 patients underwent CEA. The SAPT group consisted of 245 patients and the DAPT group consisted of 1208 patients. No difference in restenosis was identified between groups at less than 6 weeks (6.5% vs. 11.7% 50-79% stenosis, 0% vs. 2.2% 80-99% stenosis, 2.2% vs. 0.6% occlusion, p = 0.368), and 6 weeks to 2 years (20.6% vs. 17.9% 50-79% stenosis, 1.1% vs. 1.0% 80-99% stenosis, 1.6% vs. 0.4% occlusion, p = 0.242). A higher rate of restenosis in SAPT was found greater than 2 years from surgery (68.4% vs. 82.4% 50% stenosis vs. 17.6% of the DAPT group (adjusted OR 0.48, 95% CI 0.30-0.76, p = 0.002). In a propensity matched-population, 32.7% of the SAPT group demonstrated restenosis vs. 13.7% of the DAPT group (adjusted OR 0.35, 95% CI 0.16-0.77, p = 0.009). There was no difference in the need for reintervention between study groups (DAPT 3.8% vs SAPT 3.3%, p = 0.684). Conclusion: Following CEA, patients on DAPT exhibited lower rates of late restenosis. Despite this finding, a clinical difference in reintervention was not found during this study period.

Purpose: Within the millennial population cohort, identify groups reporting increased risk of nonspecific psychological distress. As the largest living population cohort, taking stock of health and well-being early is necessary as substantial national resources may be needed as this cohort ages. Design: The 2017 National Health Interview Survey data, an annual multipurpose survey of the US population, was used. Sample: A sample of 7303 respondents were created by limiting data set to birth years 1980 to 1998. Measures: Outcomes were feeling like everything is an effort, worthlessness, hopelessness, restlessness, nervousness, and sadness. Combined these statements of feeling make up a measure of nonspecific psychological distress, past 30 days. Analysis: A logistic regression was performed on each outcome. All models controlled for demographic variables known to be associated with psychological distress. Results: Females are 1.4 times more likely than males to report nonspecific psychological distress ( P < .001), whereas Hispanics and Blacks are less likely to report nonspecific psychological distress (odds ratio [OR] = 0.49, OR = 0.57, P < .001). American Indians were less likely to report worthlessness (OR = 0.30, P < .05). However, multiple race individuals increasingly reported hopelessness (OR = 1.55, P < .05). Young adults are less likely than emerging adults to report sadness (OR = 0.85, P < .05). Conclusion: In this sample, racial/ethnic groups fared better than referent groups. Health programs need to integrate intersectional identities into promotion of mental health.

Objective To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects. Methods De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations. Results We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups. Interpretation Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials.

Our objective was to determine the influence of a high-fat diet (HFD) on fasting and postprandial skeletal muscle substrate metabolism in endurance-trained (ET) compared with sedentary (SED) humans. SED ( n = 17) and ET ( n = 7) males were control-fed a 10-day moderate-fat diet followed by a 5-day isocaloric HFD (55% fat, 30% carbohydrate). Skeletal muscle biopsies were taken in the fasted condition and 4 h after a high-fat meal (820 kcals; 63% fat and 25% carbohydrate). Palmitate-induced suppression of pyruvate oxidation, an indication of substrate preference, and oxidation of fat and glucose were measured in homogenized skeletal muscle in fasted and fed states. Postprandial responses were calculated as percent changes from fasting to fed states. Postprandial suppression of pyruvate oxidation was maintained after the HFD in ET, but not SED skeletal muscle, suggesting greater adaptability to dietary intake changes in the former. Fasting total fat oxidation increased due to the HFD in ET skeletal muscle ( P = 0.006), which was driven by incomplete fat oxidation ( P = 0.008). Fasting fat oxidation remained unchanged in skeletal muscle of SED individuals. Yet, postprandial fat oxidation was similar between groups. Fasting glucose oxidation was elevated after the HFD in ET ( P = 0.036), but not SED, skeletal muscle. Postprandial glucose oxidation was reduced due to the HFD in SED ( P = 0.002), but not ET, skeletal muscle. These findings provide insight into differing substrate metabolism responses between SED and ET individuals and highlight the role that the prevailing diet may play in modulating fasting and postprandial metabolic responses in skeletal muscle.NEW & NOTEWORTHY The relationship between high dietary fat intake and physical activity level and their combined effect on skeletal muscle substrate metabolism remains unclear. We assessed the influence of the prevailing diet in modulating substrate oxidation in skeletal muscle of endurance-trained compared with sedentary humans during a high-fat challenge meal. Collectively, our findings demonstrate the adaptability of skeletal muscle in endurance-trained individuals to high dietary fat intake.

BACKGROUND AND AIMS: We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. APPROACH AND RESULTS: Unbound (“free”) bilirubin (B(f)) was measured in patient sera to characterize the binding of unconjugated bilirubin (B(T)) to albumin (A) and validate their molar concentration ratio (B(T)/A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B(T)/A at least 30% below intravascular B(T) binding capacity (i.e., B(T)/A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L(f)) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B(T) (R(2) = 0.71) and B(T)/A (R(2) = 0.76), and B(f) as a percentage of B(T) correlated inversely to the bilirubin–albumin equilibrium association binding constant (R(2) = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B(T) ≥ 30 mg/dL and B(T)/A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 μW/cm(2•)nm for 9.2 ± 1.1 hours/day kept B(T) and B(T)/A within safe limits throughout childhood, but B(T) increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B(T) and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. CONCLUSION: Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder. (Hepatology 2020;71:1923-1939).

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Both lower motor neuron loss and the deposition of phosphorylated TDP-43 inclusions display regional patterning along the spinal cord. The blood-spinal cord barrier (BSCB) ordinarily restricts entry into the spinal cord parenchyma of blood components that are neurotoxic, but in ALS there is evidence for barrier breakdown. Here we sought to examine whether BSCB breakdown, motor neuron loss, and TDP-43 proteinopathy display the same regional patterning across and along the spinal cord.MethodsWe measured cerebrospinal fluid (CSF) hemoglobin in living ALS patients (n=87 controls, n=236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. We then immunostained cervical, thoracic, and lumbar post mortem spinal cord tissue (n=5 controls, n=13 ALS) and employed semi-automated imaging and analysis to quantify and map lower motor neuron loss and phosphorylated TDP-43 inclusion load against hemoglobin leakage.ResultsMotor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the ventral grey (lamina IX) of the cervical and lumbar cord. In contrast, hemoglobin leakage was observed along the ALS spinal cord axis but was most severe in the dorsal grey and white matter in the thoracic spinal cord.ConclusionsOur data show that leakage of the blood-spinal cord barrier occurs during life but at end-stage its distribution is independent from the major motor neuron pathology and is unlikely to be a major contributor to pathogenesis in ALS.

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism.Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes.Methods: In total, 240 overweight/obese (BMI 25 – 40 kg/m2) men and women (age 40 – 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either “No MIR/LIR,” “MIR,” “LIR,” or “combined MIR/LIR.” Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet.Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.

The use of social media (SoMe) in medicine has demonstrated the ability to advance networking among clinicians and other healthcare staff, disseminate research, increase access to up-to-date information, and inform and engage medical trainees and the public at-large. With increasing SoMe use by vascular surgeons and other vascular specialists, it is important to uphold core tenets of our commitment to our patients by protecting their privacy, encouraging appropriate consent and use of any patient-related imagery, and disclosing relevant conflicts of interest. Additionally, we recognize the potential for negative interactions online regarding differing opinions on optimal treatment options for patients. The Society for Vascular Surgery (SVS) is committed to supporting appropriate and effective use of SoMe content that is honest, well-informed, and accurate. The Young Surgeons Committee of the SVS convened a diverse writing group of SVS members to help guide novice as well as veteran SoMe users on best practices for advancing medical knowledge-sharing in an online environment. These recommendations are presented here with the goal of elevating patient privacy and physician transparency, while also offering support and resources for infrequent SoMe users to increase their engagement with each other in new, virtual formats.

The Wisconsin School Violence and Bullying Prevention Study, funded by the National Institutes of Justice (NIJ), was a two-year case-control study in 24 Wisconsin middle schools (11 experimental; 13 control) seeking to understand the impact of a comprehensive bullying prevention program on bullying victimization rates. Participating schools’ bullying prevention programs were assessed at baseline and project-end using the Wisconsin Bullying Prevention Program Assessment Tool (BPPAT). This self-assessment tool, developed prior to the start of the research project, was developed by the Wisconsin Department of Public Instruction (DPI) and partners throughout Wisconsin. The BPPAT is an open-source 42-item assessment tool across 9 topic areas focused on policies and procedures with minimal financial and logistical burdens towards implementation. By design, it acknowledges wide variance across schools and districts for current practices and provides guidance, going forward, for program improvement. In the accompanying study, experimental schools were instructed to, with technical assistance, enhance their program by filling gaps identified through their completion of the BPPAT over two school years. A significant enhancement resulted among all schools, experimental and control, between 2015 and 2017 with a spill-over effect due to data collection requirements reducing programmatic differences between groups. Experimental schools reported significant declines in verified incidents of bullying with a non-significant decline among control schools. From this project, researchers determined that (1) schools are able to make program improvements in a short time period and (2) this concerted, and largely non-prescriptive, effort can have a positive and measurable impact on bullying victimization at this age group. Broader implications for the BPPAT and its use are preliminary and next steps are discussed and recommendations made.

Objective. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. Design. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. Results. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6–12 months prior to disease among SOD1 A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a FUS c.521del6 mutation and a C9ORF72 hexanucleotide repeat expansion. Conclusions. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.

Introduction Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. Methods In this retrospective study, cohorts were randomly selected from Flatiron Health’s database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (N = 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (N = 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used. Results A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months [95% confidence interval (CI) 14, 19]. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman’s rho 0.65–0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. Conclusions RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data. Funding Flatiron Health Inc., which is an independent subsidiary of the Roche group. Electronic supplementary material The online version of this article (10.1007/s12325-019-00970-1) contains supplementary material, which is available to authorized users.

Introduction/aims We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Methods Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to 3 tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 weeks in a double-blind fashion for 16 weeks and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the IL6R gene. Results Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P Discussion Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL6R C allele. These results warrant further study in ALS patients where IL6R genotype and CRP levels may be useful enrichment biomarkers. Classification of evidence This study provides Class I evidence that tocilizumab therapy is safe and well tolerated in ALS patients with high mRNA expression of inflammatory markers. Clinical trial registration Registered at ClinicalTrials.gov (NCT02469896). This article is protected by copyright. All rights reserved.

Introduction Professional conferences are where research findings are initially presented. Studies suggest many research ideas presented at conferences are never published. Previous studies have demonstrated that the full publication rate of abstracts presented at pharmacy meetings is approximately 20%. The objective of this study was to determine the full publication rate of hematology/oncology abstracts presented at major pharmacy organization annual meetings. Methods A systematic search of PubMed and Google Scholar was performed. Publication status was evaluated for hematology/oncology abstracts presented at annual meetings for the following organizations: American College of Clinical Pharmacy Annual Meeting, American Society of Health-System Pharmacists Midyear Clinical Meeting, Hematology/Oncology Pharmacy Association Annual Meeting, and International Society of Oncology Pharmacy Practitioners Annual Meeting. Data collected included the meeting of abstract presentation, number of authors, abstract study type, country of origin, journal of publication, and type of publication. Abstracts presented as trainee research were excluded. Results Of 451 oncology abstracts evaluated, the most common topic categories included pharmacotherapy (n = 244; 54.1%), clinical pharmacy practice (n = 84; 18.6%), and operational/compounding (n = 69; 15.3%). The overall publication rate was 17.5% (n = 79). Abstracts were published as full manuscripts over a spread of 48 different journals. Factors associated with full publication included abstracts with more than 5 authors (OR 3.86, 95% CI 2.32-6.43; p Conclusion This study showed an overall publication rate of 17.5% for abstracts presented at pharmacy meetings, consistent with prior studies.

ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.

Introduction Effectiveness metrics for real-word research, analogous to clinical trial ones, are needed. This study aimed to develop a real-world response (rwR) variable applicable to solid tumors and to evaluate its clinical relevance and meaningfulness. Methods This retrospective study used patient cohorts with advanced non-small cell lung cancer from a nationwide, de-identified electronic health record (EHR)-derived database. Disease burden information abstracted manually was classified into response categories anchored to discrete therapy lines (per patient-line). In part 1, we quantified the feasibility and reliability of data capture, and estimated the association between rwR status and real-world progression-free survival (rwPFS) and real-world overall survival (rwOS). In part 2, we investigated the correlation between published clinical trial overall response rates (ORRs) and real-world response rates (rwRRs) from corresponding real-world patient cohorts. Results In part 1, 85.4% of patients (N = 3248) had at least one radiographic assessment documented. Median abstraction time per patient-line was 15.0 min (IQR 7.8–28.1). Inter-abstractor agreement on presence/absence of at least one assessment was 0.94 (95% CI 0.92–0.96; n = 503 patient-lines abstracted in duplicate); inter-abstractor agreement on best confirmed response category was 0.82 (95% CI 0.78–0.86; n = 384 with at least one captured assessment). Confirmed responders at a 3-month landmark showed significantly lower risk of death and progression in rwOS and rwPFS analyses across all line settings. In part 2, rwRRs (from 12 rw cohorts) showed a high correlation with trial ORRs (Spearman’s ρ = 0.99). Conclusions We developed a rwR variable generated from clinician assessments documented in EHRs following radiographic evaluations. This variable provides clinically meaningful information and may provide a real-world measure of treatment effectiveness. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01659-0.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006-2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989-2018) were identified by NBS and treated with natural protein restriction (1.0-1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973-2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.

The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

The Academy of Nutrition and Dietetics Evidence Analysis Center conducted a systematic review of the literature to develop an evidence-based practice guideline for primary nutrition issues in cystic fibrosis (CF). This guideline is designed to complement and build upon existing evidence-based CF nutrition guidelines. The objective of this guideline was to provide recommendations for registered dietitian nutritionists in the United States delivering medical nutrition therapy to individuals with CF and their families that fill gaps in current evidence-based guidelines on topics that are crucial in order to improve health and prevent disease progression. This guideline provides 28 nutrition recommendations to guide medical nutrition therapy, including nutrition screening, nutrition assessment, and dietary intake. For topics outside the scope of this guideline, practitioners are referred to external, evidence-based recommendations. The CF landscape is evolving rapidly with breakthroughs in cystic fibrosis transmembrane regulator modulators changing CF at a cellular level. Medical nutrition therapy for individuals with CF from infancy through advanced age requires novel and individualized approaches. The Academy Evidence Analysis Library CF guidelines provide a framework for expanding upon current knowledge to determine effective nutrition strategies for individuals with CF through long and healthy futures.

Objectives: Significantly elevated levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) have been described in the blood and cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients. The aim of this study was to evaluate the analytical performance of different neurofilament assays in a round robin with 10 centers across Europe/U.S. Methods: Serum, plasma and CSF samples from a group of five ALS and five neurological control patients were distributed across 10 international specialist neurochemical laboratories for analysis by a range of commercial and in-house neurofilament assays. The performance of all assays was evaluated for their ability to differentiate between the groups. The inter-assay coefficient of variation was calculated where appropriate from sample measurements performed across multiple laboratories using the same assay. Results: All assays could differentiate ALS patients from controls in CSF. Inter-assay coefficient of variation of analytical platforms performed across multiple laboratories varied between 6.5% and 41.9%. Conclusions: This study is encouraging for the growing momentum toward integration of neurofilament measurement into the specialized ALS clinic. It demonstrates the importance of 'round robin' studies necessary to ensure the analytical quality required for translation to the routine clinical setting. A standardized neurofilament probe is needed which can be used as international benchmark for analytical performance in ALS. ispartof: Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration vol:21 issue:5-6 pages:452-458 ispartof: location:England status: published

Background Variation in opioid prescribing rates among geographic regions is well known and, to the authors’ knowledge, there have been no studies of variation from 1 dental clinic to another, and such variation might suggest an excess of opioid prescriptions. Methods The authors used a retrospective cohort design study of all dental encounter records for 819,453 soldiers in the dental clinics (n = 250) of the US Military Health System during the period from 2008 through 2017. Results There were 743,459 dental surgical encounters. Opioid prescriptions were filled for 36.7% of these encounters. Multinomial multilevel regression found statistically significant between-facility variance in opioid prescribing, which was partially explained via facility-level characteristics (region, type, and percentage of surgeries for young patients), and practice variables (mean percentage extractions, percentage periodontic surgery, and percentage specialists). Conclusions The authors found a substantial variation in opioid prescribing among dental clinics in the US Military Health System. Dentists at 11 of the 30 largest military treatment facilities prescribed at a rate 4 percentage points higher than expected, and dentists at 9 of these military treatment facilities had a rate of 4 percentage points lower than expected. Additional study of the factors allowing the low-prescribing facilities to achieve these rates might lead to an overall decrease in opioid prescribing. Practical Implications The authors’ findings of dental opioid prescribing in the military can lead to appreciation of the guidelines from the American Dental Association and the American Association of Oral and Maxillofacial Surgeons, which suggest alternatives to opioid prescribing for surgical procedures, particularly for tooth extractions.

ObjectivesTo identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.MethodsThis is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration–approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale–Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.ResultsThe study is estimated to be completed in 2022 with an interim analysis planned.ConclusionsFindings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

There is a strong positive association between nutrition status and lung function in cystic fibrosis (CF). Improvements in clinical care have increased longevity for individuals with CF, and it is unknown how cystic fibrosis transmembrane regulator (CFTR) modulation therapy affects nutrition status over time. The objective of this systematic review of the literature was to examine anthropometric (height, weight, and body mass index [BMI; calculated as kg/m2]) and body composition outcomes of CFTR modulation therapy. A literature search of Medline (Ovid), Embase, and CINAHL (EBSCO) databases was conducted for randomized controlled trials examining the effect of CFTR modulation therapy on anthropometric and body composition parameters, published in peer-reviewed journals from January 2002 until May 2018. Articles were screened, data were synthesized qualitatively, and evidence quality was graded by a team of content experts and systematic review methodologists. Significant weight gain with ivacaftor was noted in children and adults with at least 1 copy of G551D mutation. In adults with at least 1 copy of R117H the effect of ivacaftor on BMI was not significant. Effects on BMI were mixed in adults with class II mutations taking ivacaftor with lumacaftor. There was no significant change in BMI in children homozygous for F508del who took ivacaftor with tezacaftor. Elexacaftor-tezacaftor-ivacaftor increased BMI and body weight in individuals 12 years of age and older who were hetero- or homozygous for the F508del mutation. The effect of CFTR modulation therapy on anthropometric parameters depends on the genetic mutation and the type of modulation therapy used. More research is needed to understand the long-term clinical impact of these drugs on nutritional status, including body composition and the role of dietary intake.

Pathological renal mass is uncommon in children. It is important to differentiate this from a benign mass or mass-like lesion (pseudomass) for proper management. Renal dysplasia is a common finding in patients with end stage renal disease and can mimic a renal mass. Here, we report a 16-year-old girl on hemodialysis who was found to have a nodular right renal mass in the sonogram. Magnetic resonance imaging confirmed the nodular mass. She underwent right nephrectomy and the histopathology revealed features of renal dysplasia and end stage kidney disease without any evidence of malignancy. No further treatments were necessary. This case demonstrates that a nodular renal mass in dialysis patients does not always mean malignancy and could be a pseudomass from severe renal dysplasia. Since a sonogram may not be able to clearly define the etiology of solid mass in these patients, further evaluations including a renal histology and/or other imaging modalities are often necessary.

Background During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury. Methods Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury. Results Initial studies of myocardial tissues from patients with ischemic heart disease showed increased ERBB1 protein (1.12 ± 0.24 vs. 13.01 ± 2.20, P < 0.001). In contrast, ERBB1 transcript was unchanged. Studies using short hairpin RNA repression of Hif2A or Hif2aloxP/loxP Myosin Cre+ mice directly implicated hypoxia-inducible factor 2A in ERBB1 protein induction during hypoxia or after myocardial ischemia, respectively. Repression of RNA-binding protein 4 abolished hypoxia-inducible factor 2A–dependent induction of ERBB1 protein. Moreover, ErbB1loxP/loxP Myosin Cre+ mice experienced larger infarct sizes (22.46 ± 4.06 vs. 46.14 ± 1.81, P < 0.001) and could not be rescued via amphiregulin treatment. Conclusions These findings suggest that hypoxia-inducible factor 2A promotes transcription-independent induction of ERBB1 protein and implicates epidermal growth factor signaling in protection from myocardial ischemia and reperfusion injury. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

This Phase I study estimated the effect of a high-fat meal on the pharmacokinetics (PK) of H3B-6527, a covalent inhibitor of the fibroblast growth factor receptor (FGFR) 4 in clinical development for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. In this randomized, single center, single-dose, open-label, 2-period crossover study 12 healthy male volunteers, aged 18–55 years old, received a single 200-mg dose of H3B-6527 (capsule) following an overnight fast or a high-fat breakfast. PK samples were collected serially up to 36 h postdose. H3B-6527 concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. PK data were analyzed using a noncompartmental approach based on a mixed-effects model. The safety and tolerability of H3B-6527 were also assessed. H3B-6527 plasma exposure increased after a high-fat meal with fed/fasted ratios of the geometric means (90% confidence interval) of 174% (102–298%) for Cmax and 246% (146–415%) for AUC0–t. Food delayed and prolonged absorption of H3B-6527, with a fed/fasted ratio for tmax of 200% (137–263%). PK variability was lower under the fed condition, as illustrated by the CV% for Cmax and AUC0–t of 41.9–54.5% (fed) versus 64.3–70.4% (fasted). A single 200 mg dose of H3B-6527 was safe and generally well tolerated when administered to healthy adult males. A high-fat meal significantly increased exposure to H3B-6527, from 1.5- to 2.5-fold in the systemic circulation, compared to administration under fasted conditions. Food delayed and prolonged absorption of H3B-6527. In general, lower inter-subject variability was observed in the fed state in healthy volunteers. ClinicalTrials.gov.: NCT03424577.

BACKGROUND Inconsistent fat-free mass (FFM) and muscle strength responses have been reported in randomized clinical trials (RCTs) administering testosterone replacement therapy (TRT) to middle-aged and older men. Our objective was to conduct a meta-analysis to determine whether TRT improves FFM and muscle strength in middle-aged and older men and whether the muscular responses vary by TRT administration route. METHODS Systematic literature searches of MEDLINE/PubMed and the Cochrane Library were conducted from inception through 31 March 2017 to identify double-blind RCTs that compared intramuscular or transdermal TRT vs. placebo and that reported assessments of FFM or upper-extremity or lower-extremity strength. Studies were identified, and data were extracted and validated by three investigators, with disagreement resolved by consensus. Using a random effects model, individual effect sizes (ESs) were determined from 31 RCTs reporting FFM (sample size: n = 1213 TRT, n = 1168 placebo) and 17 reporting upper-extremity or lower-extremity strength (n = 2572 TRT, n = 2523 placebo). Heterogeneity was examined, and sensitivity analyses were performed. RESULTS When administration routes were collectively assessed, TRT was associated with increases in FFM [ES = 1.20 ± 0.15 (95% CI: 0.91, 1.49)], total body strength [ES = 0.90 ± 0.12 (0.67, 1.14)], lower-extremity strength [ES = 0.77 ± 0.16 (0.45, 1.08)], and upper-extremity strength [ES = 1.13 ± 0.18 (0.78, 1.47)] (P

Objectives: We developed a patient-level metric to quantify the frequency of documentation of AE assessment in oncology EHR-derived datasets, termed AE assessment completeness score (AACS), and evaluated its utility in a cohort of patients with metastatic breast cancer (mBC). Methods: We included 822 patients with mBC from the Flatiron Health EHR-derived de-identified database receiving palbociclib with endocrine therapy on or before 12/31/2018. We defined expected assessment windows (every 2 weeks for the first 2 months after starting palbociclib; every 4 weeks thereafter), based on palbociclib product information. AACS was calculated as the proportion of expected assessment windows with a documented assessment and dichotomized AACS as high (>75%) or low (≤75%). We calculated the prevalence of AEs of interest (via laboratory data: grades 1-4 elevated AST/ALT and grades 3/4 neutropenia [CTCAE v5.0]; via clinical documentation: first occurrence of diarrhea and deep vein thrombosis [DVT]), stratified by high/low AACS, and compared results to PALOMA-2. Results: 548 patients (67%) had ≥1 selected AE. More patients had high AACS for visits (80%; IQR: 80-100%) than for laboratory tests (ALT/AST/neutropenia: 28%/29%/39%; IQR: ∼40-80%). Patients with high AACS for any AE assessment were older and had longer palbociclib usage (both p

Objectives To identify barriers and enablers that impact access to early screening, detection, and diagnosis of breast cancer both globally and more specifically in the Middle East and North Africa (MENA) region (with a specific focus on Egypt, Jordan, Oman, Saudi Arabia, United Arab Emirates [UAE], and Kuwait) with a specific focus on the health system. Study design A systematic review of literature. Methods We conducted a systematic reviewing using the PRISMA methodology. We searched PubMed, Global Index Medicus, and EMBASE for studies on ‘breast cancer’, ‘breast neoplasm,’ or ‘screening, early detection, and early diagnosis’ as well as key words related to the following barriers: religion, culture, health literacy, lack of knowledge/awareness/understanding, attitudes, fatalism/fear, shame/embarrassment, and physician gender from January 1, 2000 until September 1, 2016. Two independent reviewers screened both titles and abstracts. The application of inclusion and exclusion criteria yielded a final list of articles. A conceptual framework was used to guide the thematic analysis and examine health system barriers and enablers to breast cancer screening at the broader macro health system level, at the health provider level, and the individual level. The analysis was conducted globally and in the MENA region. Results A total of 11,936 references were identified through the initial search strategy, of which 55 were included in the final thematic analysis. The results found the following barriers and enablers to access to breast cancer screening at the health system level, the health provider level, and the individual level: health system structures such as health insurance and care coordination systems, costs, time concerns, provider characteristics including gender of the provider, quality of care issues, medical concerns, and fear. In addition, the following seven barriers and enablers were identified at the health system or provider level as significantly impacting screening for breast cancer: (1) access to insurance, (2) physician recommendation, (3) physician gender, (4) provider characteristics, (5) having a regular provider, (6) fear of the system or procedure, and (7) knowledge of the health system. More specifically, the largest increased odds for having a mammogram was from having insurance, having a physician recommendation, type of provider (mainly gynecologist), and having regular contact with a physician. Clinical breast examinations were increased by having insurance and having regular contact with a physician. The eight studies identified from the MENA region identified barriers to breast cancer screening related to service quality, fear of pain and of cancer itself, female versus male provider, having a physician recommend the screen, cost issues as well as time and convenience of the services. Conclusions There are a number of system changes that can be made to remove barriers to breast cancer screening. Some of these system changes apply directly to MENA countries. A larger health system assessment of a country is warranted to determine which health system changes should be made to most efficiently and effectively improve access to breast cancer screening.

Aims Surgical excision of all benign vascular lesions of the breast identified by core needle biopsy has been recommended in the past to rule out a more serious lesion. In this study we investigated the clinical, radiologic, and pathologic findings in patients diagnosed with a benign vascular lesion at our institution to assess whether excision may be spared for lesions without atypia. Methods and results We searched the electronic medical record for patients with a vascular lesion of the breast diagnosed between 2000 and 2015. The study population consisted of 84 patients, 83 females and 1 male. The index diagnoses included 76 benign vascular lesions, 5 vascular lesions with cytologic atypia, and 3 angiosarcomas. A radiologist reviewed all pre and post-biopsy imaging studies; all cases had concordant radiologic and pathologic findings. Based on radiologic and histologic correlation, the vascular lesion accounted for the radiologic target in 40 (48%) cases and was deemed an incidental finding in 44 (52%). 7 of 32 (22%) targeted and 10 of 44 (23%) incidental benign vascular lesions underwent surgical excision; there were no upgrades at excision. No recurrences or clinical events were observed in patients with a targeted or incidental benign vascular lesion with a median followup of 39 months and 40.6 months, respectively. Conclusion Our data suggest that benign vascular lesions diagnosed on core biopsy with concordant radiologic and pathologic findings do not warrant surgical excision. This article is protected by copyright. All rights reserved.

Purpose The shortage of trained health care personnel has been increasing worldwide. With the physician assistant (PA) profession, created in the United States in the 1960s, expanding globally, this study sought to ascertain whether PAs can be an innovative solution to this crisis. Methods We conducted a convenience sample survey to assess the need for and acceptability of future PA professionals in Guatemala. Eighty-nine doctors, nurses, and community members from rural and urban areas of Guatemala participated in the survey. Results More urban (70%) than rural (58%) respondents found it difficult to access a doctor, with cost being the major reason (34%). Access in rural areas was reportedly limited by lack of doctors and inaccessible office hours. Conclusions Most survey respondents considered PAs to be suitable and potentially helpful providers for Guatemala, with a preference for competencies in the diagnosis of serious illnesses, drug prescription, labor and delivery attendance, and care for injuries and fractures, especially in rural locations. Belonging to the community was deemed very important for a PA who would practice in the country.

Objectives Oral diseases are very prevalent across the lifespan and impact overall health, yet are largely preventable. The Smiles for Life (SFL) curriculum was created to educate healthcare providers about oral disease and support integration of oral health and primary care. This study examines SFL's influence on clinical practice and education. Methods Surveys were sent to registered users of SFL. Users who self-identified as direct care providers (DCPs), or educators, were included in the analysis. Results Survey response rate was 18 percent, with 87 percent identifying as DCPs and 13 percent as educators. Across professions, 85 percent of DCPs reported SFL influencing their practice to some degree, with variance among profession type and experience. DCPs most commonly reported that SFL led them to improve how they conduct oral health activities, with 60 percent performing the activity more skillfully following completion of SFL. Fluoride varnish application was the most common practice behavior initiated, and caries risk assessments was the oral health activity affected to the greatest degree. A majority of educators (94 percent) reported that SFL led them to incorporate or enhance oral health in their teaching. SFL helped educators emphasize the importance of oral health, improved their ability to teach content, raised motivation, and reduced barriers to teaching oral health. Conclusions Data supports that SFL is positively influencing oral health practice across professions, especially in areas of caries risk assessment and fluoride varnish application. SFL improves the frequency and quality with which DCPs and educators participate in oral health activities, and facilitates oral health inclusion in primary care.

Background: The 21-gene recurrence score (RS) estimates the likelihood of distant recurrence and the benefit from chemotherapy in patients with early-stage node-negative, estrogen receptor (ER)-positive, HER2-negative breast carcinoma. The use of the assay resulted in a substantial reduction in adjuvant chemotherapy usage. In this study, we reviewed the outcome of patients with node-negative, ER+/HER2- breast cancer and low recurrence score treated at our center to further verify the prognostic value of the assay. Design: We identified breast cancer patients treated at our center between 09/2008 and 08/2013 with ER-positive, HER2-negative breast cancer and known RS. We reviewed clinicopathological characteristics, RS, treatment and outcome data. The Institutional Review Board approved the study. Results: We identified 1406 consecutive patients with early stage node negative ER+/HER2- breast cancer and low RS [RS 0-10: 510 (36%), RS 11-17: 896 (64%)] in the study period. The median age at breast cancer diagnosis was 56 years (range 22-90). Sixty-three (4%) patients were Conclusion: Our results suggest that young age ( Table 1. Clinicopathologic characteristics of the 6 patients with ER-positive, HER2-negative, node-negative breast carcinoma of recurrence score Citation Format: Wen HY, Krystel-¬Whittemore M, Patil S, Pareja F, Bowser ZL, Dickler M, Norton L, Morrow M, Hudis C, Brogi E. Breast carcinoma with 21-gene recurrence score lower than 18: Rate of distant metastases in a large series with clinical follow-up [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-14.

Diphtheria is an acute toxin-mediated superficial infection of the respiratory tract or skin caused by the aerobic gram-positive bacillus Corynebacterium diphtheriae. The epidemiology of infection and clinical manifestations of the disease vary in different parts of the world. Historical accounts of diphtheria epidemics have been described in many parts of the world since antiquity. Developed in the late 19th century, the diphtheria antitoxin (DAT) played a pivotal role in the history of public health and vaccinology prior to the advent of the diphtheria-tetanus toxoids and acellular pertussis (DTaP) vaccine. One of the most significant demonstrations of the importance of DAT was its use in the 1925 diphtheria epidemic of Nome, Alaska. Coordinated emergency delivery of this life-saving antitoxin by dog-sled relay in the harshest of conditions has left a profound legacy in the annals of vaccinology and public health. Lead dogs Balto and Togo, and the dog-led antitoxin run of 1925 represent a dynamic illustration of the contribution made by non-human species towards mass immunization in the history of vaccinology. This unique example of cooperative interspecies fellowship and collaboration highlights the importance of the human-animal bond in the one-health initiative.

Background: Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses in skeletal muscle in young, healthy male humans. Purpose: The purpose of the present study was to determine if a short-term high fat diet: 1) increases intestinal permeability and, in turn, fasting endotoxin concentrations and 2) decreases postprandial skeletal muscle fat oxidation. Methods: Thirteen normal weight young adult males (BMI 23.1 +/- 0.8 kg/m(2), age 22.2 +/- 0.4 years) were fed a control diet (55% carbohydrate, 30% fat, 9% of which was saturated, 15% protein) for two weeks, followed by 5 days of an isocaloric HFD (30% carbohydrate, 55% fat, 25% of which was saturated, 15% protein, isocaloric to the control diet). Intestinal permeability (via four sugar probe test) was assessed in the fasting state. Both before and after the HFD, a high fat meal challenge (HFM, 820 kcal, 25% carbohydrate, 63% fat, 26% of which was saturated, and 12% protein) was administered. After an overnight fast, blood samples were collected before and every hour for 4 h after the HFM to assess endotoxin, and other serum blood measures. Muscle biopsies were obtained from the vastus lateralis before and 4 h after the HFM in order to assess substrate oxidation (glucose, fatty acid and pyruvate) using radiolabeled techniques. Insulin sensitivity was assessed via intravenous glucose tolerance test. Intestinal permeability, blood samples and muscle biopsies were assessed in the same manner before and following the HFD. Main findings: Intestinal permeability was not affected by HFD (p > 0.05), but fasting endotoxin increased two fold following the HFD (p = 0.04). Glucose oxidation and fatty acid oxidation in skeletal muscle homogenates significantly increased after the HFM before the HFD (+97%, and +106% respectively) but declined after the HFM following 5 days of the HFD (-24% and +16% respectively). Fatty acid suppressibility of pyruvate oxidation increased significantly after the HFM (+32%) but this physiological effect was abolished following 5 days of the HFD (+7%). Insulin sensitivity did not change following the HFD. Conclusion: These findings demonstrate that in healthy young men, consuming an isocaloric HFD for 5 days increases fasting endotoxin, independent of changes in gut permeability. These changes in endotoxin are accompanied by a broad effect on skeletal muscle substrate metabolism including increases in postprandial fat oxidation. Importantly, the latter occurs independent of changes in body weight and whole-body insulin sensitivity. Clinical Science and Epidemiology Award from the American Diabetes Association [ADA 1-13-CE-16] This work was supported by a Clinical Science and Epidemiology Award from the American Diabetes Association, ADA 1-13-CE-16 (Hulver).

Aging, geriatrics, gerontology, and related areas are important areas of research as the population of older people increases in relationship to the total population. Researchers in these fields would benefit from guidance regarding sources for publishing and finding relevant scholarly journals and articles. Multiple database sites of journals were searched to provide a list of relevant publications. This list was expanded via perusal of published citation lists and searches in general search engines. A total of 243 journals were identified and examined. Of those journals, 198 journals are currently publishing and 45 journals have ceased publication. In terms of publication medium, 39% of the currently publishing journals are online-only, 4% are print-only and 59% of the journals publish both online and in print. Journals with aging in the title represent 36%, geriatrics 30% and gerontology 23%. Less than 10% have been identified as predatory journals. An expected increase in journals in the broad field of aging is indicated by the 49% of listed titles beginning in 2000 or later. This recent increase in available journals provides a need for the information listed in this paper.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder in which patients are at high risk for both pulmonary and systemic complications of their disease. Medical nutrition therapy by a registered dietitian nutritionist can be an integral component of lifestyle treatment targeted at maintaining and improving outcomes, such as lung function, mortality, and quality of life. The Academy of Nutrition and Dietetics (Academy) convened an expert workgroup to conduct a systematic review to update the COPD Evidence-Based Nutrition Practice Guideline. This publication outlines the Academy's Evidence Analysis Library methods used to complete the systematic review and guideline and examines the recommendations and supporting evidence. A total of 14 recommendations were developed based on evidence from eight conclusions. Using the Nutrition Care Process as a framework for practice, recommendations rated as strong included assessing and monitoring and evaluating body weight and medical nutrition therapy by a registered dietitian nutritionist. Weak recommendations included predicting resting and total energy expenditure. All other recommendations were rated as fair. These included individualizing the calorie prescription and macronutrient composition of the diet; assessing and monitoring and evaluating energy intake, serum 25-hydroxyvitamin D levels, and frequency of exacerbations; and determining need for vitamin D supplementation. Fewer than one-third of the systematic review's conclusions could be used to support the recommendations due to conflicting results or limited or no evidence available. The Evidence Analysis Library 2019 COPD Evidence-Based Nutrition Practice Guideline is a valuable resource for registered dietitian nutritionists and other health care professionals caring for those with COPD.

OBJECTIVES: Individuals with cystic fibrosis (CF) are at high risk for malnutrition and poor growth. New drugs that modulate CF transmembrane receptor (CFTR) function are available, although their effects on anthropometric parameters are not clear. This systematic review aimed to determine if various CFTR modulator therapies affect weight and growth parameters in individuals with CF. METHODS: A literature search was conducted using MEDLINE, CINAHL and Embase databases for peer-reviewed, randomized controlled trials (RCT) published from January 2002 to May 2018 that examined the effect of CFTR modulation therapy on weight and growth parameters in children and adults with CF. Articles were screened for relevance, data was extracted and summarized, and risk of bias was assessed to determine the quality of evidence. RESULTS: A total of 612 original articles were identified, and 13 articles representing 10 RCTs were included in qualitative synthesis and three were included in quantitative synthesis. All but one RCT demonstrated low risk of bias. The targeted class of CFTR mutation varied by RCT. Studies indicated that, in children and adults with CF with class III mutations, ivacaftor treatment alone increased weight and BMI (4 RCTs), but it did not influence growth in individuals with class II (1 RCT) or class IV mutations (1 RCT). Treatment with ivacaftor + lumacaftor in adults homozygous for the F508del CFTR mutation (class II) increased BMI following 24 weeks of treatment (2 RCTs), but there was no effect in adults heterozygous for the mutation treated for 8 weeks (1 RCT). Treatment with lumacaftor + tezacaftor in individuals ages 12–20 years with class II mutations did not change growth parameters (1 RCT). CONCLUSIONS: Effects of CFTR modulators on increasing weight and growth in individuals with CF are likely dependent on the therapy formulation (single vs combination therapy) and the targeted CFTR mutation. Whereas ivacaftor alone increases weight and growth parameters in individuals with class III mutations, ivacaftor + lumacaftor is more effective at increasing BMI in adults homozygous for the class II F508del CFTR mutation. Additional studies are needed to determine effects of other CFTR modulator drugs on growth parameters in individuals with varying CFTR mutations. FUNDING SOURCES: Academy of Nutrition and Dietetics/Medical Nutrition DPG, National Institutes of Health.

ObjectiveTo test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp358Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers.MethodsAn observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype.ResultsPatients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019).ConclusionsTheses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies.

Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are collected in clinical trials. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a traditional RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. In this retrospective study, cohorts were randomly selected from Flatiron Health’s database of patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach was tested for feasibility (N=26). Three non-RECIST abstraction approaches were tested for feasibility, reliability, and validity (N=200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. RECIST-based cancer progression could be ascertained from the EHRs of 23% of patients (6/26). In 87% of patients (173/200), at least one rwP event was identified using both the radiology- and clinician-anchored approaches. rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months (95% confidence interval [CI]: 14, 19). Median real-world progression-free survival (rwPFS) was 5.5 (95% CI: 4.6, 6.3) and 4.9 months (95% CI: 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman’s rho: 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. RECIST cannot adequately assess cancer progression in EHR-derived data due to missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data.

Cannabis sativa (Cannabis) is one of the world’s most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.

BACKGROUND A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. RESULTS A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged

BACKGROUND The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC). METHODS This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC. RESULTS The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months). CONCLUSIONS The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819–2827. © 2016 American Cancer Society