Publications by authors named "Shervin Tabrizi"

16 Publications

  • Page 1 of 1

Assessment of Simulated SARS-CoV-2 Infection and Mortality Risk Associated With Radiation Therapy Among Patients in 8 Randomized Clinical Trials.

JAMA Netw Open 2021 03 1;4(3):e213304. Epub 2021 Mar 1.

Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts.

Importance: During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown.

Objective: To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT).

Design, Setting, And Participants: This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020.

Exposures: COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs).

Main Outcomes And Measures: Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios.

Results: Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%).

Conclusions And Relevance: In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3304DOI Listing
March 2021

Doublecortin Expression in Prostate Adenocarcinoma and Neuroendocrine Tumors.

Int J Radiat Oncol Biol Phys 2020 11 22;108(4):936-940. Epub 2020 Jun 22.

Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and histologic grade and clinical outcome. We sought to evaluate the relationship between DCX expression and these variables in human prostate cancer.

Methods And Materials: DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC) and compared across disease states, histologic grades, and clinical outcomes. Biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and overall survival (OS) were analyzed using Cox proportional hazards.

Results: DCX expression was not significantly different among normal prostate (n = 29), primary prostate cancer (n = 131), and metastases (n = 19) and did not increase with grade in a large cohort of radical prostatectomy samples (n = 17,967). Those with DCX expression above and below the median did not have significant differences in BRFS (HR 1.15 [95% confidence interval, 0.88-1.49], P = .31), MFS (HR 1.2 [0.84-1.7], P = .3), or OS (HR 1.15 [0.7-1.84], P = .56). In a cohort with untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n = 10) compared with grade group 5 prostate adenocarcinoma (n = 110) (P = .007). Similarly, in 2 cohorts with mCRPC (n = 290), DCX expression was higher in lesions with neuroendocrine features compared with adenocarcinoma (P < .001).

Conclusions: Contrary to recent data using mouse models, DCX expression did not differ by disease state or outcome and did not increase with grade in a large data set of patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine histology, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX and its clinical significance in prostate cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.024DOI Listing
November 2020

A Quantitative Framework for Modeling COVID-19 Risk During Adjuvant Therapy Using Published Randomized Trials of Glioblastoma in the Elderly.

Neuro Oncol 2020 Apr 27. Epub 2020 Apr 27.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Background: During the ongoing COVID-19 pandemic, contact with the healthcare system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We re-analyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes.

Methods: We extracted individual patient-level data (IPLD) for 1,321 patients from Kaplan-Meier curves from five randomized trials on treatment of elderly GBM patients including available subanalyses based on MGMT methylation status. We simulated trial data with incorporation of COVID-19 associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate.

Results: Our simulations reveal how COVID-19-associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19-associated risk.

Conclusions: Incorporation of COVID-19-associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision-making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology.
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http://dx.doi.org/10.1093/neuonc/noaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197582PMC
April 2020

The path forward for radiation therapy in the management of low-grade gliomas.

Neuro Oncol 2020 06;22(6):748-749

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1093/neuonc/noaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283024PMC
June 2020

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Authors:
Lauren A Eberly Aaron Richterman Anne G Beckett Bram Wispelwey Regan H Marsh Emily C Cleveland Manchanda Cindy Y Chang Robert J Glynn Katherine C Brooks Robert Boxer Rose Kakoza Jennifer Goldsmith Joseph Loscalzo Michelle Morse Eldrin F Lewis Samantha Abel Ayrenne Adams Joseph Anaya Erik H Andrews Benjamin Atkinson Viswatej Avutu Alexandra Bachorik Omar Badri Mariel Bailey Katie Baird Salina Bakshi Denis Balaban Kenneth Barshop Emily Baumrin Omar Bayomy Julia Beamesderfer Nora Becker David D Berg Adam N Berman Steven M Blum Alexander P Boardman Kaeleen Boden Robert A Bonacci Sarah Brown Kirsti Campbell Siobhan Case Emily Cetrone Alexandra Charrow David Chiang Devin Clark Aaron J Cohen Alissa Cooper Tomas Cordova C Nicholas Cuneo Alsina Alejandro de Feria Karen Deffenbacher Ersilia M DeFilippis Geneva DeGregorio Aaron J Deutsch Bradford Diephuis Sanjay Divakaran Peter Dorschner Nicholas Downing Caitlin Drescher Kristin M D'Silva Peter Dunbar David Duong Sarah Earp Christine Eckhardt Scott A Elman Ross England Kay Everett Natalie Fedotova Tamara Feingold-Link Mark Ferreira Herrick Fisher Patricia Foo Michael Foote Idalid Franco Thomas Gilliland Jacqueline Greb Katherine Greco Sungat Grewal Benjamin Grin Matthew E Growdon Brendan Guercio Cynthia K Hahn Brian Hasselfeld Erika J Haydu Zachary Hermes Gordon Hildick-Smith Zachary Holcomb Kathryn Holroyd Laura Horton George Huang Stanley Jablonski Douglas Jacobs Nina Jain Sohan Japa Richard Joseph Mariya Kalashnikova Neil Kalwani Daniel Kang Abraar Karan Joel T Katz Daniel Kellner Khameer Kidia June-Ho Kim Scott M Knowles Laura Kolbe Idil Kore Yiannis Koullias Ifedayo Kuye Joshua Lang Matthew Lawlor Melissa G Lechner Ken Lee Scott Lee Zachary Lee Neha Limaye Stephanie Lin-Beckford Marla Lipsyc Jessica Little Julia Loewenthal Ranjani Logaraj Diana M Lopez Daniel Loriaux Yi Lu Kevin Ma Nareh Marukian Wilfredo Matias Jared R Mayers Ian McConnell Michael McLaughlin Christina Meade Catherine Meador Anish Mehta Elizabeth Messenger Constantinos Michaelidis Jacob Mirsky Emilie Mitten Alisa Mueller Jyotsna Mullur Amir Munir Emily Murphy Ellen Nagami Abirami Natarajan Michelle Nsahlai Chijioke Nze Noreen Okwara Peter Olds Rafael Paez Michael Pardo Siddharth Patel Alec Petersen Laura Phelan Erica Pimenta Daniel Pipilas Molly Plovanich Denise Pong Brian W Powers Anita Rao Haiyan Ramirez Batlle Mattheus Ramsis Anna Reichardt Sheridan Reiger Michelle Rengarajan Stephanie Rico Benjamin N Rome Rachael Rosales Lisa Rotenstein Alexis Roy Sarah Royston Hallie Rozansky Meghan Rudder Christine E Ryan Sanjay Salgado Pablo Sanchez Jennifer Schulte Aswin Sekar Nicholas Semenkovich Evan Shannon Neil Shaw Andrew Ben Shorten William Shrauner Lauren Sinnenberg James W Smithy Gregory Snyder Anirudh Sreekrishnan Hans Stabenau Eleni Stavrou Andrew Stergachis Robert Stern Alexander Stone Shervin Tabrizi Sam Tanyos Cristina Thomas Haley Thun Kristine Torres-Lockhart An Tran Carolyn Treasure Frederick D Tsai Stephen Tsaur Evan Tschirhart Justin Tuwatananurak Ramkumar V Venkateswaran Anastasia Vishnevetsky Lindsay Wahl April Wall Frances Wallace Elisa Walsh Priscilla Wang Heather B Ward Lindsay N Warner Lachelle D Weeks Kipp Weiskopf Jordan Wengrod Jessica N Williams Marisa Winkler Jeffrey L Wong Devin Worster Aileen Wright Caroline Wunsch Jamila S Wynter Chase Yarbrough Wai-Ying Yau Daniel Yazdi Jennifer Yeh Maria A Yialamas Nicholas Yozamp Marina Zambrotta Rebecca Zon

Circ Heart Fail 2019 11 29;12(11):e006214. Epub 2019 Oct 29.

Division of Cardiovascular Medicine, and Department of Medicine (E.F..L.), Brigham and Women's Hospital, Boston, MA.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality.

Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.

Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183732PMC
November 2019

Identifying gene expression programs of cell-type identity and cellular activity with single-cell RNA-Seq.

Elife 2019 07 8;8. Epub 2019 Jul 8.

Department of Systems Biology, Harvard Medical School, Boston, United States.

Identifying gene expression programs underlying both cell-type identity and cellular activities (e.g. life-cycle processes, responses to environmental cues) is crucial for understanding the organization of cells and tissues. Although single-cell RNA-Seq (scRNA-Seq) can quantify transcripts in individual cells, each cell's expression profile may be a mixture of both types of programs, making them difficult to disentangle. Here, we benchmark and enhance the use of matrix factorization to solve this problem. We show with simulations that a method we call consensus non-negative matrix factorization (cNMF) accurately infers identity and activity programs, including their relative contributions in each cell. To illustrate the insights this approach enables, we apply it to published brain organoid and visual cortex scRNA-Seq datasets; cNMF refines cell types and identifies both expected (e.g. cell cycle and hypoxia) and novel activity programs, including programs that may underlie a neurosecretory phenotype and synaptogenesis.
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http://dx.doi.org/10.7554/eLife.43803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639075PMC
July 2019

Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma.

Radiother Oncol 2019 08 10;137:95-101. Epub 2019 May 10.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, USA. Electronic address:

Background: Patients with low-grade gliomas (LGG) can survive years with their illness. Proton radiotherapy (PRT) can reduce off-target dose and decrease the risk of treatment-related morbidity. We examined long-term morbidity following proton therapy in this updated prospective cohort of patients with LGG.

Methods: Twenty patients with LGG were enrolled prospectively and received PRT to 54 Gy(RBE) in 30 fractions. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, quality of life, and survival outcomes were performed up to 5 years following treatment.

Results: Six patients died (all of disease) and six had progression of disease. Median follow-up was 6.8 years for the 14 patients alive at time of reporting. Median progression-free survival (PFS) was 4.5 years. Of tumors tested for molecular markers, 71% carried the IDH1-R132H mutation and 29% had 1p/19q co-deletion. There was no overall decline in neurocognitive function; however, a subset of five patients with reported cognitive symptoms after radiation therapy had progressively worse function by neurocognitive testing. Six patients developed neuroendocrine deficiencies, five of which received Dmax ≥20 Gy(RBE) to the hypothalamus-pituitary axis (HPA). Most long-term toxicities developed within 2 years after radiation therapy.

Conclusions: The majority of patients with LGG who received proton therapy retained stable cognitive and neuroendocrine function. The IDH1-R132H mutation was present in the majority, while 1p/19q loss was present in a minority. A subset of patients developed neuroendocrine deficiencies and was more common in those with higher dose to the HPA.
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http://dx.doi.org/10.1016/j.radonc.2019.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642836PMC
August 2019

Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study.

Lancet Infect Dis 2018 06 6;18(6):684-695. Epub 2018 Mar 6.

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Maryland, MD, USA; Harvard School of Public Health, Boston, MA, USA.

Background: Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause differences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever.

Methods: We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality.

Findings: Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1·4 times increase in mortality risk for each 10 years of age (p=0·00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0·00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4·63 [SD 1·04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8·6 for patients without clinical history of fluid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1·3; p=0·046), aspartate aminotransferase (OR 1·5; p=0·075), and potassium (OR 3·6; p=0·0024) were independent predictors of death.

Interpretation: Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might significantly reduce mortality.

Funding: German Research Foundation, German Center for Infection Research, Howard Hughes Medical Institute, US National Institutes of Health, and World Bank.
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http://dx.doi.org/10.1016/S1473-3099(18)30121-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984133PMC
June 2018

Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus.

Cell 2015 Aug;162(4):738-50

FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address:

The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2015.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537774PMC
August 2015

Lassa fever in post-conflict sierra leone.

PLoS Negl Trop Dis 2014 Mar 20;8(3):e2748. Epub 2014 Mar 20.

Department of Microbiology and Immunology, Tulane University, New Orleans, Louisiana, United States of America; Broad Institute, Cambridge, Massachusetts, United States of America; Zalgen Labs, LLC, Germantown, Maryland, United States of America.

Background: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease.

Methodology/principal Findings: Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects.

Conclusions/significance: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF.
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http://dx.doi.org/10.1371/journal.pntd.0002748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961205PMC
March 2014

Natural selection in a bangladeshi population from the cholera-endemic ganges river delta.

Sci Transl Med 2013 Jul;5(192):192ra86

Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

As an ancient disease with high fatality, cholera has likely exerted strong selective pressure on affected human populations. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera. We identified 305 candidate selected regions using the composite of multiple signals (CMS) method. The regions were enriched for potassium channel genes involved in cyclic adenosine monophosphate-mediated chloride secretion and for components of the innate immune system involved in nuclear factor κB (NF-κB) signaling. We demonstrate that a number of these strongly selected genes are associated with cholera susceptibility in two separate cohorts. We further identify repeated examples of selection and association in an NF-κB/inflammasome-dependent pathway that is activated in vitro by Vibrio cholerae. Our findings shed light on the genetic basis of cholera resistance in a population from the Ganges River Delta and present a promising approach for identifying genetic factors influencing susceptibility to infectious diseases.
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http://dx.doi.org/10.1126/scitranslmed.3006338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367964PMC
July 2013

Identifying recent adaptations in large-scale genomic data.

Cell 2013 Feb;152(4):703-13

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated with susceptibility to infectious disease and other phenotypes. We experimentally characterized one candidate nonsynonymous variant in Toll-like receptor 5 (TLR5) and show that it leads to altered NF-κB signaling in response to bacterial flagellin. PAPERFLICK:
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674781PMC
http://dx.doi.org/10.1016/j.cell.2013.01.035DOI Listing
February 2013

Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever.

Philos Trans R Soc Lond B Biol Sci 2012 Mar;367(1590):868-77

Department of Organismic and Evolutionary Biology, FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.

Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit.
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http://dx.doi.org/10.1098/rstb.2011.0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267117PMC
March 2012

Early assessment of a new integrated preclinical musculoskeletal curriculum at a medical school.

Am J Orthop (Belle Mead NJ) 2011 Jan;40(1):14-8

Harvard Medical Center, Boston, MA, USA.

Increased incidence of musculoskeletal conditions and medical students' deficiencies in musculoskeletal knowledge have been a cause for concern for educators in this field. Findings from a 2005 study conducted at our institution revealed that medical students, despite acknowledging the importance of musculoskeletal education, have inadequate knowledge and skill in this system. In response to these findings, additions to the preclinical musculoskeletal curriculum were designed and instituted. Medical students were assessed at the end of the new curriculum, using the same evaluation tools that had been administered before the curricular changes, and responses from the second-year students who completed the entire new preclinical curriculum were compared with those of students who had completed the old curriculum. Results showed that students reported significantly higher levels of clinical confidence in performing physical examinations of several anatomical regions of the musculoskeletal system. A notable proportion of students cited weaknesses in other fields, such as anatomy, as a prominent contributor to their lack of confidence in the musculoskeletal system.
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January 2011

Complications of low-profile dorsal versus volar locking plates in the distal radius: a comparative study.

J Hand Surg Am 2011 Jul;36(7):1135-41

Beth Israel Deaconess Medical Center and the Harvard Medical School, Boston, MA 02215, USA.

Purpose: Dorsal plating of distal radius fractures with traditional 2.5-mm-thick plates is associated with extensor tendon complications. Consequently, volar locking plates have gained widespread acceptance. A new generation of 1.2- to 1.5-mm, low-profile dorsal plates was designed to minimize tendon irritation. This study examines the complication rates of low-profile dorsal plates compared with volar locking plates.

Methods: We identified patients with distal radius fractures treated between September 2002 and June 2006 by low-profile dorsal or volar locking plates. Information pertaining to 7 categories of complications (hardware discomfort and pain, tendon irritation/rupture, failure of reduction, infection, complex regional pain syndrome, stiffness, and neuropathy/hypersensitivity) was collected. Complications were defined as any postoperative plating complications requiring additional surgical intervention, whereas those that only caused patient discomfort were considered secondary problems.

Results: We included 100 patients, comprising 104 plating cases (57 dorsal, 47 volar), in this study. Overall length of follow-up was 44 ± 21 months (range, 12-80 mo). A total of 18 patients (8 dorsal, 10 volar) experienced complications, whereas 47 (25 dorsal, 22 volar) had secondary reports. Three dorsal and 4 volar patients had complete plate removals. Three dorsal and no volar plates had screw removals only. One volar plate (no dorsal plates) had a major tendon rupture (flexor pollicis longus); 3 dorsal and 3 volar plates resulted in tendon irritation complications, and 4 dorsal and 3 volar plates had secondary problems from tendon irritation. None of the above measures approached statistical significance. Volar cases were associated with significantly more neuropathic complications than dorsal cases.

Conclusions: Dorsal low-profile plates are not associated with significantly more tendon irritation or rupture complications. However, volar plating is associated with a higher rate of neuropathic complications.

Type Of Study/level Of Evidence: Therapeutic III.
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http://dx.doi.org/10.1016/j.jhsa.2011.04.004DOI Listing
July 2011

Effectiveness of the AAOS Leadership Fellows Program for Orthopaedic Surgeons.

J Bone Joint Surg Am 2010 Nov;92(16):2700-8

Department of Orthopaedic Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue - Stoneman 10, Boston, MA 02215, USA.

Background: Effective physician leadership is critical to the future success of healthcare organizations. The American Academy of Orthopaedic Surgeons (AAOS) Leadership Fellows Program is a one-year program designed to train young orthopaedic surgeons to become future leaders in orthopaedics. The purpose of this study was to evaluate the impact of the AAOS Leadership Fellows Program on the leadership skills and achievements of its participants.

Methods: Graduates of the Leadership Fellows Program were compared with a control group of previous applicants who were not accepted to the program (applicants) in a retrospective cohort comparison study. A subjective survey of leadership skills was used to assess the confidence of the two cohorts in eight areas of leadership. In addition, an updated curriculum vitae from each of sixty leadership fellows from the classes of 2003 through 2009 and from each of forty-seven applicants was retrospectively reviewed for evidence of leadership. The updated curriculum vitae of the leadership fellows was evaluated for leadership activity attained prior to and following participation in the program, while the updated curriculum vitae of applicants was evaluated for leadership activity attained prior to and following the last year of application to the program. Curricula vitae were assessed for demonstration of national leadership, academic rank, hospital administrative rank, and research experience.

Results: On the leadership survey, the graduates of the Leadership Fellows Program scored higher than the applicants in seven of eight categories. The review of the curricula vitae demonstrated that, prior to the Leadership Fellows Program, the leadership fellows were more likely than the applicants to have an academic practice and hold an academic rank. The difference between the two cohorts in administrative rank and leadership of national committees was not significant. Following the program, the leadership fellows were more likely to chair national committees (p < 0.001) and hold leadership positions in their hospitals (p = 0.008). Furthermore, the leadership fellows were more likely to advance in their academic and administrative ranks compared with those who applied to the program and were not accepted.

Conclusions: The AAOS Leadership Fellows Program seems to have a positive impact on the leadership competency of its participants. Graduates of the program are more likely to assume leadership positions in national organizations and within their own institutions.
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http://dx.doi.org/10.2106/JBJS.J.00272DOI Listing
November 2010