University of California, San Francisco
  • San Francisco, CA, United States
Recent publications
Major neurological and psychiatric diseases affect females and males differently, suggesting that inherent sex-biased biological factors affect disease incidence and progression. These factors are grouped into two major groups, hormones secreted by the gonads, and genes unequally encoded on X and Y sex chromosomes in the two sexes. Numerous rodent models of these diseases have been used to dissect the relative contributions of sex hormones and sex chromosomes, and studies of humans bear strongly on the factors that might account for the sex differences. Examples of research progress in this area are reviewed for multiple sclerosis and autoimmune diseases, stroke, Alzheimer's Disease, Parkinson's Disease, and autism spectrum disorder. The study of sex differences offers novel perspectives in the discovery of factors that may be targeted in the clinic to alleviate the burden of these diseases.
Experts have described ways to improve peer review quality. Perspectives from expert reviewers are largely absent in the health professions education literature. To gather guidance from expert reviewers, to aid authors striving to publish and reviewers aiming to perform their task effectively. This study surveyed the Journal of Graduate Medical Education (JGME) ‘Top Reviewers’ from 2017, 2018, and 2019. ‘Top Reviewers’ perform four or more reviews per year, with high average ratings. Top reviewers were sent an 11-item survey in February 2020. The survey included three demographic questions and eight open-ended, free-text questions about the concepts reviewers most often target in their reviews. We calculated descriptive statistics and performed a thematic analysis of open-ended responses. Of 62 eligible top reviewers, 44 (71%) responded to the survey. Only eight (18.2%) and seven (15.9%) respondents reported having ‘stock phrases’ or a reviewer template used for reviewer feedback to authors, respectively. The what (research question, methods), how (presentation, writing), and why (relevance, impact) were the resulting themes summarizing how reviewers categorized and responded to common problems. For ‘really good papers’ reviewers found the what acceptable and focused on how and why. For ‘really bad’ papers, reviewers focused on big picture feedback, such as the value of the study. Top reviewers from a single health professions education journal appear to have similar approaches to conducting reviews. While most do not use stock phrases or templates, they share similar strategies to differentiate ‘good’ vs. ‘bad’ papers through the what, why, and how of a manuscript.
Background: Dental personnel are at risk of developing occupational contact dermatitis. Objectives: The aims of the study were to determine prevalence of occupational contact dermatitis in dental personnel referred for patch testing and to characterize relevant allergens and sources. Methods: The study used a retrospective, cross-sectional analysis of the North American Contact Dermatitis Group (NACDG) data, 2001-2018. Results: Of 41,109 patients, 585 (1.4%) were dental personnel. Dental personnel were significantly more likely than nondental personnel to be female (75.7% vs 67.4%, P < 0.0001), have occupationally related dermatitis (35.7% vs 11.5%, P < 0.0001), and/or have primary hand involvement (48.6% vs 22.5%, P < 0.0001). More than one quarter of dental personnel (62/585, 27.7%) had 1 or more occupationally related allergic patch test reaction(s). There were 249 occupationally related reactions to NACDG screening allergens, most commonly glutaraldehyde (18.1%), thiuram mix (16.1%), and carba mix (14.1%). The most common sources of NACDG screening allergens were gloves (30.7%), dental materials (26.6%), and sterilizing solutions (13.1%). Seventy-three dental personnel (12.5%) had 1 or more positive patch test reactions to occupationally related allergen(s)/substances not on the screening series. Occupationally related irritant contact dermatitis was identified in 22.2% (n = 130) of dental personnel, most commonly to nonskin soaps/detergents/disinfectants (32.0%). Conclusions: Occupational contact dermatitis is common in dental personnel referred for patch testing. Comprehensive testing beyond screening series is important in these patients.
Background: Shoe contact allergy can be difficult to diagnose and manage. Objective: The aim of the study was to characterize demographics, clinical characteristics, patch test results, and occupational data for the North American Contact Dermatitis Group patients with shoe contact allergy. Methods: This is a retrospective study of 33,661 patients, patch tested from 2005 to 2018, with a shoe source, foot as 1 of 3 sites of dermatitis, and final primary diagnosis of allergic contact dermatitis. Results: Three hundred fifty-two patients met the inclusion criteria. They were more likely to be male (odds ratio = 3.36, confidence interval = 2.71-4.17) and less likely to be older than 40 years (odds ratio = 0.49, confidence interval = 0.40-0.61) compared with others with positive patch test reactions. The most common relevant North American Contact Dermatitis Group screening allergens were potassium dichromate (29.8%), p-tert-butylphenol formaldehyde resin (20.1%), thiuram mix (13.3%), mixed dialkyl thioureas (12.6%), and carba mix (12%). A total of 29.8% (105/352) had positive patch test reactions to supplemental allergens, and 12.2% (43/352) only had reactions to supplemental allergens. Conclusions: Shoe contact allergy was more common in younger and male patients. Potassium dichromate and p-tert-butylphenol formaldehyde resin were the top shoe allergens. Testing supplemental allergens, personal care products, and shoe components should be part of a comprehensive evaluation of suspected shoe contact allergy.
Introduction DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos. Results We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10 ⁻⁷ in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 ( MAP3K6 , p = 6.13 × 10 ⁻⁸ ) showed significant association with pre-bronchodilator Tiffeneau–Pinelli index, the probes cg00914963 ( TBC1D16 , p = 1.04 × 10 ⁻⁷ ), cg16405908 ( MRGPRE , p = 2.05 × 10 ⁻⁸ ) , and cg07428101 ( MUC2 , p = 5.02 × 10 ⁻⁹ ) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 ( KCNJ6 ) with post-bronchodilator Tiffeneau–Pinelli index ( p = 1.13 × 10 ⁻⁸ ). However, these markers did not show significant associations in publicly available data from Europeans ( p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau–Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations. Conclusions We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.
Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a Patient-Reported Outcome Measure (PROM) used to evaluate the health status of patients with heart failure (HF) but has predominantly been tested in settings serving predominately white, male, and economically well-resourced populations. We sought to examine the acceptability of the shorter version of the KCCQ (KCCQ-12) among racially and ethnically diverse patients receiving care in an urban, safety-net setting. Methods We conducted cognitive interviews with a diverse population of patients with heart failure in a safety net system to assess their perceptions of the KCCQ-12. We conducted a thematic analysis of the qualitative data then mapped themes to the Capability, Opportunity, Motivation Model of Behavior framework. Results We interviewed 18 patients with heart failure and found that patients broadly endorsed the concepts of the KCCQ-12 with minor suggestions to improve the instrument’s content and appearance. Although patients accepted the KCCQ-12, we found that the instrument did not adequately measure aspects of health care and quality of life that patients identified as being important components of managing their heart failure. Patient-important factors of heart failure management coalesced into three main themes: social support, health care environment, and mental health. Conclusions Patients from this diverse, low-income, majority non-white population experience unique challenges and circumstances that impact their ability to manage disease. In this study, patients were receptive to the KCCQ-12 as a tool but perceived that it did not adequately capture key health components such as mental health and social relationships that deeply impact their ability to manage HF. Further study on the incorporation of social determinants of health into PROMs could make them more useful tools in evaluating and managing HF in diverse, underserved populations.
Although it is widely recognized that strong program management is essential to achieving better health outcomes, this priority is not recognized in malaria programmatic practices. Increased management precision offers the opportunity to improve the effectiveness of malaria interventions, overcoming operational barriers to intervention coverage and accelerating the path to elimination. Here we propose a combined approach involving quality improvement, quality management, and participative process improvement, which we refer to as Combined Quality and Process Improvement (CQPI), to improve upon malaria program management. We draw on evidence from other areas of public health, as well as pilot implementation studies in Eswatini, Namibia and Zimbabwe to support the proposal. Summaries of the methodological approaches employed in the pilot studies, overview of activities and an outline of lessons learned from the implementation of CQPI are provided. Our findings suggest that a malaria management strategy that prioritizes quality and participative process improvements at the district-level can strengthen teamwork and communication while enabling the empowerment of subnational staff to solve service delivery challenges. Despite the promise of CQPI, however, policy makers and donors are not aware of its potential. Investments are therefore needed to allow CQPI to come to fruition.
Background Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC. Methods and results We used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients ( N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97–1.00; CD8T: HR = 0.97, 95% CI = 0.95–1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00–1.07; mdNLR: HR = 1.12, 95% CI = 1.04–1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death ( P < 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites. Conclusions Our results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence.
Aim To describe the spectrum of parasagittal injury on MRI studies performed on children following severe perinatal term hypoxia–ischaemia, using a novel MRI grading system, and propose a new central pattern correlated with neuropathologic features. Methods MR scans of 297 patients with perinatal term hypoxia–ischaemia were evaluated for typical patterns of brain injury. A total of 83 patients that demonstrated the central/basal ganglia–thalamus and perirolandic pattern of injury were categorised according to the degree of severity. The perirolandic injury was graded by the degree of interhemispheric widening, paracentral lobule involvement and perirolandic cortex destruction leading to a tiered categorisation. Of these 83 patients, 19 had the most severe subtype of injury. A detailed analysis of the clinical data of a subset of 11 of these 19 patients was conducted. Results We demonstrated the mild subtype in 21/83(25%), the moderate subtype in 22/83(27%) and the severe subtype in 21/83(25%). A fourth pattern was identified in 19/83(23%) patients with a diamond-shaped expansion of the interhemispheric fissure, concomitant thalamic, putaminal, hippocampal and other smaller substrate involvement indicative of the most destructive subtype. Conclusions We propose a new MR grading system of injury at the parasagittal perirolandic region related to severe, sustained central perinatal term hypoxia–ischaemia. We also introduce a previously undescribed pattern of injury, the most severe form of this spectrum, seen especially after prolongation of the second stage of labour. This constellation of high metabolic substrate, targeted tissue destruction is consistently demonstrated by MRI, termed the massive paramedian injury pattern.
Zika virus (ZIKV) is a mosquito-borne arbovirus that can cause severe congenital birth defects. The utmost goal of ZIKV vaccines is to prevent both maternal-fetal infection and congenital Zika syndrome. A Zika purified inactivated virus (ZPIV) was previously shown to be protective in non-pregnant mice and rhesus macaques. In this study, we further examined the efficacy of ZPIV against ZIKV infection during pregnancy in immunocompetent C57BL6 mice and common marmoset monkeys ( Callithrix jacchus ). We showed that, in C57BL/6 mice, ZPIV significantly reduced ZIKV-induced fetal malformations. Protection of fetuses was positively correlated with virus-neutralizing antibody levels. In marmosets, the vaccine prevented vertical transmission of ZIKV and elicited neutralizing antibodies that remained above a previously determined threshold of protection for up to 18 months. These proof-of-concept studies demonstrate ZPIV’s protective efficacy is both potent and durable and has the potential to prevent the harmful consequence of ZIKV infection during pregnancy.
Background: Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. Methods: A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. Results: The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43-6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18-5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27-6.46, p = 0.011). Conclusions: Familiarity with postnatal ERT increased respondents' likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT.
Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget’s disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group’s conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.
There is increasing attention being given to opportunities and approaches to advance health equity using implementation science. To reduce disparities in health, it is crucial that an equity lens is integrated from the earliest stages of the implementation process. In this paper, we outline four key pre-implementation steps and associated questions for implementation researchers to consider that may help guide selection and design of interventions and associated implementation strategies that are most likely to reach and be effective in reducing health disparities among vulnerable persons and communities.
Background Tbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density. However, an understanding of Tbr1 ’s function in the adult mouse brain remains elusive. Methods We used conditional mutagenesis to interrogate Tbr1 ’s function in cortical layers 5 and 6 of the adult mouse cortex. Results Adult Tbr1 CKO mutants have dendritic spine and synaptic deficits as well as reduced frequency of mEPSCs and mIPSCs. LiCl, a WNT signaling agonist, robustly rescues the dendritic spine maturation, synaptic defects, and excitatory and inhibitory synaptic transmission deficits. Conclusions LiCl treatment could be used as a therapeutic approach for some cases of ASD with deficits in synaptic transmission.
Background Aneurysms are rare anomalies of the portomesenteric venous system. Thrombotic complications of these lesions can lead to mesenteric venous ischemia and bowel infarction, potentially requiring surgical intervention. Herein we describe a case of mesenteric ischemia due to a large thrombosed portomesenteric aneurysm treated with endovascular techniques. Case presentation A 37-year-old previously healthy male who presented with abdominal pain to his local emergency department was found to have a thrombosed 12.0 × 5.1 cm portomesenteric venous aneurysm with evidence of mesenteric ischemia on CT. When conservative management with anticoagulation failed, transhepatic pharmacomechanical thrombolysis was initially performed. This was followed by TIPS placement with additional trans-TIPS thrombectomy to improve sluggish portal outflow and prevent re-thrombosis. The patient’s symptoms and imaging findings of ischemia resolved after endovascular therapy. No surgical intervention was required, and the patient was discharged on enoxaparin before being transitioned to apixaban. The TIPS remained patent at 2-year follow-up, with no change in the size of the aneurysm or re-thrombosis noted. The patient’s synthetic liver function was preserved with no evidence of hepatic encephalopathy during the follow-up period. Conclusions Endovascular therapies may be used to manage thrombotic complications of portomesenteric venous aneurysms, obviating the need for surgical intervention in selected patients.
Mendelian randomization (MR) is a term that applies to the use of genetic variation to address causal questions about how modifiable exposures influence different outcomes. The principles of MR are based on Mendel’s laws of inheritance and instrumental variable estimation methods, which enable the inference of causal effects in the presence of unobserved confounding. In this Primer, we outline the principles of MR, the instrumental variable conditions underlying MR estimation and some of the methods used for estimation. We go on to discuss how the assumptions underlying an MR study can be assessed and describe methods of estimation that are robust to certain violations of these assumptions. We give examples of a range of studies in which MR has been applied, the limitations of current methods of analysis and the outlook for MR in the future. The differences between the assumptions required for MR analysis and other forms of epidemiological studies means that MR can be used as part of a triangulation across multiple sources of evidence for causal inference. Mendelian randomization is a technique for using genetic variation to examine the causal effect of a modifiable exposure on an outcome such as disease status. This Primer by Sanderson et al. explains the concepts of and the conditions required for Mendelian randomization analysis, describes key examples of its application and looks towards applying the technique to growing genomic datasets.
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9,618 members
Efstathios D Gennatas
  • Department of Epidemiology and Biostatistics
Raunak Shrestha
  • Department of Radiation Oncology
Mohammad Kazem Fallahzadeh
  • Division of Nephrology
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Susan Desmond-Hellmann
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www.ucsf.edu
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