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Abstract The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection.

Background: Diabetes will be the 7th leading cause of death by 2030 as per the World Health Organization (WHO). Encouraging the populace to use drugs rationally is the main goal of research on drug usage. Aims and Objectives: The objective of this study is to determine drug utilization pattern among patients with diabetes mellitus using the WHO Core Indicators in a tertiary care hospital, Indore. Materials and Methods: A prospective and observational study was done in the Department of Pharmacology along with the Department of Medicine in MGM Medical College and Hospital, Indore. After taking informed consent from diabetic patients visiting the outpatient department, their demographic details and prescriptions were recorded in case record form and analyzed using WHO core indicators. Results: In our study, total prescription assessed was 123. The total drugs prescribed were 652, out of which a total of 278 were anti-diabetic drugs. The average number of drugs per encounter was 5.3. Percentage of drugs prescribed by generic name = 92.4%. Percentage of encounters with an antibiotic prescribed = 10.5%. Percentage of encounters with an injection prescribed = 34.9%. The percentage of drugs prescribed from the essential drugs list (2015) = 72.3%. Conclusion: Prescribing pattern of antidiabetic drugs vary a little from the WHO standards. Rational prescription should be encouraged and such studies should be done regularly for periodic auditing of prescription. [ABSTRACT FROM AUTHOR]

Metformin-associated lactic acidosis (MALA) is a rare and potentially life-threatening complication of metformin use. It typically occurs in patients who are diabetic and also have other risk factors for lactic acidosis, including kidney and liver conditions, malignancy, or use of certain medications. We report a case of MALA in a man in his 70s with diabetes who presented with gradually worsening gastrointestinal symptoms, including severe abdominal pain and nausea. He reported these symptoms in the setting of metformin use with an acute kidney injury (AKI), likely brought on by poor oral intake and excessive antibiotic use for a urinary tract infection. He was promptly started on intravenous fluids with a bicarbonate drip to concurrently treat his prerenal AKI and lactic acidosis, which resulted in rapid resolution of his symptoms. Renal function normalised within 12 days of admission. Since diabetic patients commonly use metformin and are also at higher risk of renal dysfunction, this case highlights the vulnerability of this group of patients and the need for increased knowledge and awareness of MALA. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to genotype two previously identified SNPs (rs1048661:R141L, and rs3825942:G153D) in the lysyl oxidase-like 1 (LOXL1) gene and determine their association with pseudoexfoliation glaucoma (XFG) in patients from Pune, India. Methods: All subjects underwent detailed phenotyping, and DNA extraction was performed on blood samples by using standardized techniques. Exon 1 of the LOXL1 gene containing the SNPs (rs3825942:G153D; rs1048661:R141L) were Sanger sequenced, and the results were analyzed using sequence analysis software SeqScape 2.1.1. Results: Data were analyzed from 71 patients with XFG and 81 disease-negative, age-matched controls. There was a strong association between the G allele of rs3825942 and XFG with an odds ratio of 10.2 (CI: 3.92–26.6; P < 0.001). The G allele of rs1048661 also showed an increase in risk relative to the T allele (OR = 1.49; CI: 0.88–2.51; P = 0.13), but this was not significant. Haplotype combination frequencies were estimated for rs1048661 and rs3825942; the GG haplotype was associated with a significant increase in risk (OR = 3.91; CI: 2.27–6.73; P < 0.001). Both the GA and TG haplotypes were associated with decreased XFG risk, although the latter was not significant (GA: OR = 0.08; CI: 0.03–0.21; P < 0.001; TG: OR = 0.67; CI: 0.40–1.13; P = 0.13). Conclusion: The risk G allele in rs3852942 (G153D) is strongly associated with the development of XFG in the Western Indian population. Genetic screening strategies to identify LOXL1 risk alleles in the population can assist in case definition and early diagnosis, targeting precious resources to high-risk patients.

Coronary artery aneurysms are extremely rare, major causative factors associated with this condition are atherosclerosis, trauma, connective tissue disorders, vasculitis, idiopathic, mycotic, and congenital. We present a case of a 49-year-old male who underwent primary angioplasty for acute ST-elevation myocardial infarction and presented with chest pain, fresh ST elevation, and fever after 10 days of the index procedure. The patient was suspected to have subacute stent thrombosis along with some infective pathology. However, work up did not reveal any systemic localization, and blood cultures were negative. Coronary angiogram showed aneurysm of the left anterior descending artery (LAD) with Grade 3 thrombus in the proximal part of stent with thrombolysis in myocardial infarction (TIMI) II antegrade flow. A two-dimensional echo revealed mild left ventricular dysfunction with moderate pericardial effusion. Cardiac positron emission tomography scan confirmed the suspicion of a stent-related mycotic aneurysm. Therefore, the patient was managed with intravenous antibiotics, antiplatelets, and low-molecular-weight heparin, followed by newer oral anticoagulants.

Abstract FLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD+ AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD+ AML patients.

This paper aims to investigate the learners learning experiences and difficulties of ESL among the UKM undergraduates. This study will be focusing on identifying the factors behind Malaysian undergraduate's experiences and also their difficulties in the English as Second Language (ESL) classroom. This paper discusses some of the issues of English language learning experiences at the tertiary level in this country. It reflects on how the teaching of English is variously conceptualized in our classrooms, raising important questions about the positions of English literacy to Malaysian undergraduates. A qualitative research method was employed, whereby a semi-structured interview session was conducted compromising thirty Bachelor of Arts undergraduates (BA ELS). The findings of this study suggests learners at tertiary level do face challenges in their ESL classroom learning, in areas such as the learning environment itself needs to be improved, the quality of education, the academics, the role of educators and the teaching approach were among others pointed out by the learners themselves.

Reading is huge because reading is a source of information, but most of the learners open social media more often, play games with laptops or gadgets, compared to reading. Using teaching materials in supporting the teaching learning process can help students more easily understand the learning material, because it is undeniable that the development of teaching materials is very important in learning, so the more interesting the teaching materials used, the more interested students will be in the teaching materials. The purpose of this research is to determine the development of application-based teaching materials and to determine student responses to application-based teaching materials in the Church Administration and Management course in the Christian Leadership Study Program. The results of the study are calculatedbased on the validity calculation formula, then an average score of 3.1875 is obtained with decent criteria. Through this research, it is hoped that the application-based Church Administration and Management teaching program (Smart Apps Creator) is used by students as a practical learning medium and can be used anytime and anywhere

Given the widespread impacts of climate change and environmental degradation on human health, medical schools have been under increasing pressure to provide comprehensive planetary health education to their students. However, the logistics of integrating such a wide-ranging and multi-faceted topic into existing medical curricula can be daunting. In this article, we present the Warren Alpert Medical School of Brown University as an example of a student-driven, bottom-up approach to the development of a planetary health education program. In 2020, student advocacy led to the creation of a Planetary Health Task Force composed of medical students, faculty, and administrators as well as Brown Environmental Sciences faculty. Since that time, the task force has orchestrated a wide range of planetary health initiatives, including interventions targeted to the entire student body as well as opportunities catering to a subset of highly interested students who wish to engage more deeply with planetary health. The success of the task force stems from several factors, including the framing of planetary health learning objectives as concordant with the established educational priorities of the Medical School's competency-based curriculum known as the Nine Abilities, respecting limitations on curricular space, and making planetary health education relevant to local environmental and hospital issues.

Abstract The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this “general response across drugs” (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.

Integration of new DNA into cellular genomes mediates replication of retroviruses and transposons; integration reactions have also been adapted for use in human gene therapy. Tracking the distributions of integration sites is important to characterize populations of transduced cells and to monitor potential outgrow of pathogenic cell clones. Here, we describe a pipeline for quantitative analysis of integration site distributions named INSPIIRED (integration site pipeline for paired-end reads). We describe optimized biochemical steps for site isolation using Illumina paired-end sequencing, including new technology for suppressing recovery of unwanted contaminants, then software for alignment, quality control, and management of integration site sequences. During library preparation, DNAs are broken by sonication, so that after ligation-mediated PCR the number of ligation junction sites can be used to infer abundance of gene-modified cells. We generated integration sites of known positions in silico, and we describe optimization of sample processing parameters refined by comparison to truth. We also present a novel graph-theory-based method for quantifying integration sites in repeated sequences, and we characterize the consequences using synthetic and experimental data. In an accompanying paper, we describe an additional set of statistical tools for data analysis and visualization. Software is available at https://github.com/BushmanLab/INSPIIRED.

Analysis of sites of newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools for data analysis and visualization that take as input integration site data from our INSPIIRED pipeline. Paired-end sequencing allows inference of the numbers of transduced cells as well as the distributions of integration sites in target genomes. We present interactive heatmaps that allow comparison of distributions of integration sites to genomic features and that support numerous user-defined statistical tests. To summarize integration site data from human gene therapy samples, we developed a reproducible report format that catalogs sample population structure, longitudinal dynamics, and integration frequency near cancer-associated genes. We also introduce a novel summary statistic, the UC50 (unique cell progenitors contributing the most expanded 50% of progeny cell clones), which provides a single number summarizing possible clonal expansion. Using these tools, we characterize ongoing longitudinal characterization of a patient from the first trial to treat severe combined immunodeficiency-X1 (SCID-X1), showing successful reconstitution for 15 years accompanied by persistence of a cell clone with an integration site near the cancer-associated gene CCND2. Software is available at https://github.com/BushmanLab/INSPIIRED.