Perelman School of Medicine
Perelman School of Medicine's mission is to advance knowledge and improve health through research, patient care, and the education of trainees in an inclusive culture that embraces diversity, fosters innovation, stimulates critical thinking, supports lifelong learning, and sustains our legacy of excellence.
- Center for Public Health Initiatives
- Department of Biostatistics, Epidemiology and Informatics
- Department of Family Medicine and Community Health
- Department of Medical Ethics and Health Policy
- Department of Microbiology Papers
- Department of Obstetrics and Gynecology
- Department of Psychiatry
- Department of Systems Pharmacology and Translational Therapeutics
- Botswana-UPenn Partnership
- Center for Cognitive Neuroscience
- FM Kirby Center for Molecular Ophthalmology
- Global Health Programs
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Dataset Supplementary Figures for "A mechanism of CALHM1 channel gating"James Kevin Foskett; Z. MaThe Calcium Homeostasis Modulator (CALHM) proteins comprise a family of six genes, some of which have been demonstrated to function as ion channels. CALHM1, the founding member, is an extracellular Ca2+- and voltage-gated large-pore non-selective ion channel. The mechanisms by which Ca2+ and voltage regulate CALHM1 channel gating are unknown. Cryo-electron microscopic structures of CALHM1 and its paralogs have provided little insights into these features, although they have suggested that the amino-termini, including an amino-terminal helix (NTH) and the first transmembrane helix (TM1) may possess significant flexibility. Here we investigated the role of the amino terminus in gating regulation of human CALHM1 channels expressed in Xenopus oocytes. Deletion of the NTH and the proximal end of TM1 markedly reduced the voltage-dependence of channel gating, whereas extracellular Ca2+ retained ability to close the channel, indicating that the amino-terminus is not the Ca2+-regulated gate. Furthermore, inhibition of channel currents by ruthenium red was independent of the presence of the amino terminus and was mediated by effects on channel gating rather than pore block. Introduction of a cysteine residue into the proximal end of TM1 enabled complete inhibition of the channel by a crosslinking reagent under conditions in which the channel was in a closed state. Our findings indicate that while the NTH plays a role in voltage-dependent gating, it does not act as the gate itself. Instead, our results suggest that the gate in CALHM1 is formed by proximal regions of the first transmembrane domain.Dataset A mechanism of CALHM1 ion channel gating(2024-12-03) James Kevin FoskettThe Calcium Homeostasis Modulator (CALHM) proteins comprise a family of six genes, some of which have been demonstrated to function as ion channels. CALHM1, the founding member, is an extracellular Ca2+- and voltage-gated large-pore ion channel. The mechanisms by which Ca2+ and voltage regulate CALHM1 channel gating are unknown. Cryo-electron microscopic structures of CALHM1 and its paralogs have provided little insights into these features, although they have suggested that the amino-termini, including an amino-terminal helix (NTH) and the first transmembrane helix (TM1) may possess significant flexibility. Here we investigated the role of the amino terminus in gating regulation of human CALHM1 channels expressed in Xenopus oocytes. Deletion of the NTH and the proximal end of TM1 reduced the voltage-dependence of channel gating, whereas extracellular Ca2+ retained ability to close the channel, indicating that the amino-terminus is not the Ca2+-regulated gate. Furthermore, inhibition of channel currents by ruthenium red was independent of the presence of the amino terminus and was mediated by effects on channel gating rather than pore block. Introduction of a cysteine residue into the proximal end of TM1 enabled complete inhibition of the channel by a crosslinking reagent under conditions in which the channel was in a closed state. Our findings indicate that while the NTH plays a role in voltage-dependent gating, it does not act as the gate itself. Instead, our results suggest that the gate in CALHM1 is most likely formed by proximal regions of the first transmembrane domain.Publication Reducing Incarceration in Philadelphia(2017-10-01) Shefner, Ruth; Anderson, Evan; Riker, DerekReducing incarceration is an important public health priority. There is now widespread recognition that criminal justice systems are a significant source of public health harm. They sometimes penalize individuals without improving community health, or create improvements that are offset by the considerable individual and communal harms associated with incarceration and with the collateral consequences of criminal convictions. Philadelphia has become a leader in implementing criminal justice reforms. In 2010, the District Attorney’s Office initiated changes to reduce overcharging. In the last seven years, the First Judicial District has created nine specialized diversion programs, with seven specifically aimed at addressing the underlying causes of criminal activity. These programs vary in design but share key features. All attempt to prevent future criminal activity by diverting offenders away from incarceration and into community supervision. Programs also provide access to appropriate social and health services, and utilize a more collaborative approach between prosecutors, defense attorneys, judges and social services staff. This more efficient use of resources allows greater attention to more serious and violent crimes in Philadelphia.Publication Precision Prevention and Public Health(2017-11-01) McGrath, Colleen; Palmarella, Graceann; Solomon, Sara; Dupuis, RoxanneA new trend, “Precision Prevention,” is emerging in public health. This term is borrowed from “Precision Medicine,” a concept in medicine that allows for individualized treatments for patients. Precision prevention utilizes “biologic, behavioral, socioeconomic, and epidemiologic data to devise and implement strategies” tailored to specific individuals or populations. The goal of precision prevention is to target the “right intervention to the right population at the right time.” Much of precision prevention accounts for one’s social determinants of health, tailoring interventions based on a set of individual factors related to where we live, learn, work, and play that impact our health. Precision prevention works to move away from universal approaches to illness and injury prevention. Flaura Koplin Winston, MD, MPH, Chair of the Science and Medical Advisory Committee for Entrepreneurship and Innovation at The Children’s Hospital of Philadelphia (CHOP), applies a precision prevention framework, using a “tiered risk model” (see figure 1) for the Violence Prevention Initiative at CHOP. In the tiered risk model, there are three types of interventions focused around the needs of universal, selected, and indicated populations. At each level, interventions range from meeting the universal needs of the general population, to the select needs of populations at increased or different risk, and finally to interventions tailored for populations with adverse or indicated needs. For example, within the Violence Prevention Initiative, selected interventions that integrate appropriate community support services are tailored to children at greater risk for violence, and indicated interventions tailor the most intensive, direct support to child victims of violence.Publication The Opioid Crisis(2017-09-01) Stark, Caroline; Solomon, Sara; Cannuscio, Carolyn; Hom, Jeffrey; Meisel, ZacharyOpioid use and addiction have reached epidemic proportions in Philadelphia, making drug overdose involving opioids a leading cause of death. Both pharmaceutical and illicit opioids contribute to this crisis. Opioid sales in Philadelphia more than doubled between 2000 and 2012, and health care providers continue to prescribe opioid pain medication in greater quantities than medically appropriate. The peak age group for overdoses is 45-54, an older age group than previously seen. Over-prescribing of opioids contributes to the recruitment of adults into drug dependence. While use of opioid pain medications usually does not lead to opioid use disorder, four out of five heroin users nationwide transitioned from original use of prescription medications. Heroin is easy to obtain, potent and cheap compared to prescription pain medications. There are estimated to be at least 70,000 heroin users in Philadelphia.Publication Supervised Injection Facilities(2018-01-01) Shefner, Ruth; McGrath, Colleen; Sharma, Meghana; Anderson, Evan; Cocchiaro, BenjaminInjection drug use once accounted for half of the new HIV cases each year in Philadelphia. Today, it accounts for less than 6%. This achievement is the result, in large part, of increased access to sterile syringes through needle exchange at Prevention Point Philadelphia. But while tremendous strides have been made in reducing the HIV risk for people who inject drugs (PWID), the story with respect to skin and soft tissue infection (SSTI) and overdose is grim. SSTIs are life-threatening, painful, and remain common among PWID. Rates of fatal overdose, meanwhile, have skyrocketed in recent years, resulting in 907 deaths in 2016 and over 1200 in 2017. Trends for injection-related HIV and injection-related infection and overdose have taken different trajectories because access to sterile injection materials only addresses a portion of the risk environment for injection drug use. Avoiding SSTIs is hard, even with a sterile syringe, when injecting in poorly lit, cold, dirty or otherwise unhygienic spaces. Reversing an overdose is possible with naloxone, but there has to be someone to administer it, and PWID often inject in secluded spaces. Some evidence also suggests that overdose is more likely when PWID inject hurriedly – from fear of assault or arrest – and without the opportunity to taste and control dosing.Publication Advances in Digital Health Research(2018-02-01) Palmarella, Graceann; McGrath, Colleen; Solomon, Sara; Dupuis, Roxanne; Cannuscio, CarolynSocial media and emerging mobile technologies have sparked radical shifts in human behavior, with people worldwide spending an average of 2 hours and 15 minutes daily on social networks. Facebook, Instagram, and Twitter have more than 2 billion users globally. Social networking site use has risen dramatically by all age groups, with the highest use among 18-29 year olds (see Figure below). Every second, Twitter users send 6,000 tweets, amounting to 500 million tweets per day. Instagram users post approximately 95 million photos, generating 4.2 billion likes, each day. A newer platform, Snapchat, has 178 million daily users, 60% of whom are under 25 years of age. They share an average of 3 billion snaps, or rapidly vanishing photos, every day. Researchers at Penn are turning these Tweets, posts, and snaps into innovative data sources that hold vital clues about behaviors, emotions, preferences, opinions, and social networks—all with potential implications for population health. Through the analysis of keywords, images, phrases, emoticons, likes, and hashtags, Penn teams are turning troves of digital information into human-centered health interventions and educational initiatives.Publication 2014-2015 Annual Report(2015-01-01) Center for Public Health InitiativesPublication 15 Years of Public Health(2017-01-01) Center for Public Health InitiativesPublication Relationships between Clinician-Level Attributes and Fidelity-Consistent and Fidelity-Inconsistent Modifications to an Evidence-Based Psychotherapy(2015-01-01) Crits-Christoph, Paul F; Stirman, Shannon W; Gutner, Cassidy A; Evans, Arthur C; Beidas, Rinad S; Edmunds, JulieBackground: Clinicians often modify evidence-based psychotherapies (EBPs) when delivering them in routine care settings. There has been little study of factors associated with or implications of modifications to EBP protocols. This paper differentiates between fidelity-consistent and fidelity-inconsistent modifications and it examines the potential influence of two clinician characteristics, training outcomes, and attitudes toward EBPs on fidelity-consistent and fidelity-inconsistent modifications of cognitive behavioral therapy in a sample of clinicians who had been trained to deliver these treatments for children or adults. Methods: Survey and coded interview data collected 2 years after completion of training programs in cognitive behavioral therapy were used to examine associations between successful or unsuccessful completion of training, clinician attitudes, and modifications. Modifications endorsed by clinicians were categorized as fidelity-consistent or fidelity-inconsistent and entered as outcomes into separate regression models, with training success and attitudes entered as independent variables. Results: Successful completion of a training program was associated with subsequent fidelity-inconsistent modifications but not fidelity-consistent modifications. Therapists who reported greater openness to using EBPs prior to training reported more fidelity-consistent modifications at follow-up, and those who reported greater willingness to adopt EBPs if they found them appealing were more likely to make fidelity-inconsistent modifications. Conclusions: Implications of these findings for training, implementation, EBP sustainment, and future studies are discussed. Research on contextual and protocol-related factors that may impact decisions to modify EBPs will be an important future direction of study to complement to this research.