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  • Theta-gamma phase amplitude coupling in a hippocampal CA1 microcircuit.

    Ponzi, Adam; Dura-Bernal, Salvador; Migliore, Michele (2023-03-23)
    Phase amplitude coupling (PAC) between slow and fast oscillations is found throughout the brain and plays important functional roles. Its neural origin remains unclear. Experimental findings are often puzzling and sometimes contradictory. Most computational models rely on pairs of pacemaker neurons or neural populations tuned at different frequencies to produce PAC. Here, using a data-driven model of a hippocampal microcircuit, we demonstrate that PAC can naturally emerge from a single feedback mechanism involving an inhibitory and excitatory neuron population, which interplay to generate theta frequency periodic bursts of higher frequency gamma. The model suggests the conditions under which a CA1 microcircuit can operate to elicit theta-gamma PAC, and highlights the modulatory role of OLM and PVBC cells, recurrent connectivity, and short term synaptic plasticity. Surprisingly, the results suggest the experimentally testable prediction that the generation of the slow population oscillation requires the fast one and cannot occur without it.
  • Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution.

    Bobrowski-Khoury, Natasha; Sequeira, Jeffrey M; Quadros, Edward V (2023-02-25)
    In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.
  • Development of a model to predict antidepressant treatment response for depression among Veterans

    Puac-Polanco, Victor; Ziobrowski, Hannah N.; Ross, Eric L.; Liu, Howard; Turner, Brett; Cui, Ruifeng; Leung, Lucinda B.; Bossarte, Robert M.; Bryant, Corey; Joormann, Jutta; et al. (Cambridge University Press (CUP), 2022-07-15)
    Background Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA). Methods A 2018–2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample. Results In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (S.E.) of 0.66 (0.04) in the test sample. A strong gradient in probability (S.E.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors. Conclusions Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.
  • A Systematic Review of Drink Specials, Drink Special Laws, and Alcohol-Related Outcomes.

    Puac-Polanco, Victor; Keyes, Katherine M; Mauro, Pia M; Branas, Charles C (2020-10-31)
    The adverse health and safety consequences of heavy alcohol consumption are a leading problem around the world. While many risk factors have been extensively studied and presented in comprehensive summaries, not all questions regarding risk factors for problematic drinking behaviors have been answered and presented in systematic reviews. As of March 2020, no review has summarized studies assessing the role of promotional price practices at on-premises alcohol outlets, known as drink specials. Also missing was systematic information of policies that regulated these promotional practices. We aimed to synthesize the available research evidence of the effects that drink specials and drink special laws have on different alcohol-related outcomes.
  • "In Spanish": advancing public health.

    González, Mila C; Santaella, Julian; Puac-Polanco, Victor
  • A Diverse and Inclusive Academic Membership for All.

    Puac-Polanco, Victor; Morabia, Alfredo
    With the growing recognition that diversity and inclusion are essential for the improvement of science and innovation, we provide some perspectives on 3 findings of DeVilbiss et al. (Am J Epidemiol. 2020;189(10):998-1010). We provide points of discussion on factors and strategies to consider when drafting diversity and inclusion programs for the Society for Epidemiologic Research.
  • Previous violent events and mental health outcomes in Guatemala.

    Puac-Polanco, Victor D; Lopez-Soto, Victor A; Kohn, Robert; Xie, Dawei; Richmond, Therese S; Branas, Charles C (2015-02-25)
    We analyzed a probability sample of Guatemalans to determine if a relationship exists between previous violent events and development of mental health outcomes in various sociodemographic groups, as well as during and after the Guatemalan Civil War.
  • Mortality from motorcycle crashes: the baby-boomer cohort effect.

    Puac-Polanco, Victor; Keyes, Katherine M; Li, Guohua (2016-08-09)
    Motorcyclists are known to be at substantially higher risk per mile traveled of dying from crashes than car occupants. In 2014, motorcycling made up less than 1 % of person-miles traveled but 13 % of the total mortality from motor-vehicle crashes in the United States. We assessed the cohort effect of the baby-boomers (i.e., those born between 1946 and 1964) in motorcycle crash mortality from 1975 to 2014 in the United States.
  • Mental health in the Americas: an overview of the treatment gap.

    Kohn, Robert; Ali, Ali Ahsan; Puac-Polanco, Victor; Figueroa, Chantal; López-Soto, Victor; Morgan, Kristen; Saldivia, Sandra; Vicente, Benjamín (2018-10-10)
    To understand the mental health treatment gap in the Region of the Americas by examining the prevalence of mental health disorders, use of mental health services, and the global burden of disease.
  • Prescription Drug Monitoring Programs and Prescription Opioid-Related Outcomes in the United States.

    Puac-Polanco, Victor; Chihuri, Stanford; Fink, David S; Cerdá, Magdalena; Keyes, Katherine M; Li, Guohua
    Prescription drug monitoring programs (PDMPs) are a crucial component of federal and state governments' response to the opioid epidemic. Evidence about the effectiveness of PDMPs in reducing prescription opioid-related adverse outcomes is mixed. We conducted a systematic review to examine whether PDMP implementation within the United States is associated with changes in 4 prescription opioid-related outcome domains: opioid prescribing behaviors, opioid diversion and supply, opioid-related morbidity and substance-use disorders, and opioid-related deaths. We searched for eligible publications in Embase, Google Scholar, MEDLINE, and Web of Science. A total of 29 studies, published between 2009 and 2019, met the inclusion criteria. Of the 16 studies examining PDMPs and prescribing behaviors, 11 found that implementing PDMPs reduced prescribing behaviors. All 3 studies on opioid diversion and supply reported reductions in the examined outcomes. In the opioid-related morbidity and substance-use disorders domain, 7 of 8 studies found associations with prescription opioid-related outcomes. Four of 8 studies in the opioid-related deaths domain reported reduced mortality rates. Despite the mixed findings, emerging evidence supports that the implementation of state PDMPs reduces opioid prescriptions, opioid diversion and supply, and opioid-related morbidity and substance-use disorder outcomes. When PDMP characteristics were examined, mandatory access provisions were associated with reductions in prescribing behaviors, diversion outcomes, hospital admissions, substance-use disorders, and mortality rates. Inconsistencies in the evidence base across outcome domains are due to analytical approaches across studies and, to some extent, heterogeneities in PDMP policies implemented across states and over time.
  • Treatment Differences in Primary and Specialty Settings in Veterans with Major Depression.

    Puac-Polanco, Victor; Leung, Lucinda B; Bossarte, Robert M; Bryant, Corey; Keusch, Janelle N; Liu, Howard; Ziobrowski, Hannah N; Pigeon, Wilfred R; Oslin, David W; Post, Edward P; et al.
    The Veterans Health Administration (VHA) supports the nation's largest primary care-mental health integration (PC-MHI) collaborative care model to increase treatment of mild to moderate common mental disorders in primary care (PC) and refer more severe-complex cases to specialty mental health (SMH) settings. It is unclear how this treatment assignment works in practice.
  • Mental Health of Guatemalan Health Care Workers During the COVID-19 Pandemic: Baseline Findings From the HEROES Cohort Study.

    Paniagua-Avila, Alejandra; Ramírez, Dorian E; Barrera-Pérez, Aida; Calgua, Erwin; Castro, Claudia; Peralta-García, Ana; Mascayano, Franco; Susser, Ezra; Alvarado, Rubén; Puac-Polanco, Victor
    To assess the baseline prevalence of mental health conditions and associated exposures in a cohort of health care workers (HCWs) in Guatemala. We analyzed baseline information from the 2020 Web-based COVID-19 Health Care Workers Study (HEROES)-Guatemala. Outcomes included mental distress and depressive symptoms. Exposures included COVID-19 experiences, sociodemographic characteristics, and job characteristics. We used crude and adjusted Poisson regression models in our analyses. Of the 1801 HCWs who accepted to participate, 1522 (84.5%) completed the questionnaire; 1014 (66.8%) were women. Among the participants, 59.1% (95% confidence interval [CI] = 56.6, 61.5) screened positive for mental distress and 23% (95% CI = 20.9, 25.2) for moderate to severe depressive symptoms. COVID-19 experiences, sociodemographic characteristics, and job characteristics were associated with the study outcomes. Participants who were worried about COVID-19 infection were at higher risk of mental distress (relative risk [RR] = 1.47; 95% CI = 1.30, 1.66) and depressive symptoms (RR = 1.51; 95% CI = 1.17, 1.96). Similarly, the youngest participants were at elevated risk of mental distress (RR = 1.80; 95% CI = 1.24, 2.63) and depressive symptoms (OR = 4.58; 95% CI = 1.51, 13.87). Mental health conditions are highly prevalent among Guatemalan HCWs. (. 2022;112(S6):S602-S614.
  • Foveolar thickness as potential standardized structural outcome measurement in studies of Bietti crystalline dystrophy.

    Jenny, Laura A; Liu, Pei-Kang; Kolesnikova, Masha; Duong, Jimmy; Kim, Angela H; Levi, Sarah R; Greenstein, Vivienne C; Tsang, Stephen H (2022-08-29)
    Bietti crystalline dystrophy (BCD) is an ultra-rare orphan disorder that can lead to blindness. Because of the variable rates of progression of the disease, it is necessary to identify suitable outcome measurements for tracking progression in BCD. A retrospective analysis of patients with a clinical and genetic diagnosis of BCD was conducted. Four measurements of spectral domain-optical coherence tomography were compared to patients' best corrected visual acuity. We observed that patients with higher measurements of foveolar thickness, choroidal thickness in the foveolar region, ellipsoid zone band length and the outer nuclear layer + area, had on average better visual acuity. Future studies are needed to validate the structural-functional correlations we observed in BCD and to propose a sensitive and clinically meaningful outcome measurement for tracking this rare, variable disease.
  • Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence.

    Kolesnikova, Masha; Lima de Carvalho, Jose Ronaldo; Parmann, Rait; Kim, Angela H; Mahajan, Vinit B; Tsang, Stephen H; Sparrow, Janet R (2022-10-12)
    Leber congenital amaurosis (LCA) type 2, due to disease-causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec-rzyl (VN) for RPE65-associated LCA. Herein, we present the long-term follow-up of a patient treated with VN using quantitative autofluorescence (488 nm excitation).
  • Correlation of Intraoperative Ultrasonographic Oral Tongue Shape and Border and Risk of Close Margins.

    Au, Vivienne H; Yoon, Byung C; Juliano, Amy; Sadow, Peter M; Faquin, William C; Varvares, Mark A (2023-01-19)
    Intraoperative ultrasound (IOUS) is a potentially useful adjunct to the resection of oral tongue cancers (OTC). IOUS images of the tumor-normal tissue interface show different patterns of invasion. In this retrospective series of 29 patients treated for OTC, we evaluated if there was a correlation between IOUS findings of patterns of invasion and final histology and assessed if there was any associated risk of increased incidence of positive or close margins with different patterns of invasion as seen on ultrasound. Although we found no significant correlation between ultrasound patterns of invasion and histological evaluation, we did find that an infiltrative pattern of invasion on IOUS did result in a significant risk of a close margin. Further exploration of these findings in a larger prospective study could provide definitive information on the efficacy of this modality in OTC resections.
  • Gender and Sex Equity in Stroke Research, Education, and Care.

    Volpe, Salvatore G; Zuniga, Mary C; Caunca, Michelle R; Rosendale, Nicole (2023-01-23)
  • Integrating Electrical Impedance Spectroscopy into Clinical Decisions for Pigmented Skin Lesions Improves Diagnostic Accuracy: A Multitiered Study

    Litchman, Graham H; Marson, Justin W; Svoboda, Ryan M; Rigel, Darrel S (National Society for Cutaneous Medicine, 2020-08-30)
    Introduction: The number-needed-to-biopsy (NNB) metric measures the efficiency of a clinician’s ability to accurately diagnose and recommend pigmented skin lesions (PSLs) for biopsy for suspected melanomas. Electrical impedance spectroscopy (EIS) is a non-invasive technique that measures differences in resistance between healthy and cancerous skin cells, intended as an aid to enhance diagnostic accuracy. Methods: Dermatology clinicians of three distinct groups (residents, physician assistants/nurse practitioners, and practicing dermatologists) were evaluated on their ability to accurately recommend suspect PSLs for biopsy before and after the integration of EIS data. Results: All three groups had a reduction in NNB after the inclusion of EIS. Instances of missed biopsies for malignant melanoma were significantly reduced with simultaneous significant reductions in unnecessary biopsies for benign lesions. There was a material improvement of biopsy selection for PSLs having clinically challenging features. EIS also greatly improved the diagnostic acumen of clinicians whose assessments were less accurate than their peers prior to EIS incorporation. Conclusions: The integration of EIS technology into the PSL biopsy decision was demonstrated to be effective in significantly enhancing clinician NNB and more accurate PSL biopsy selection.
  • Assessment of the 31-Gene Expression Profile Test by Dermatologists: A Cross-Sectional Survey from National Dermatology Conferences

    Marson, Justin; Litchman, Graham; Svoboda, Ryan; Glazer, Alex; Farberg, Aaron; Winkelmann, Richard; Rigel, Darrell (National Society for Cutaneous Medicine, 2021-03-06)
    Background: The 31-gene expression profile (31-GEP) test uses 31 genetic markers obtained from the initial biopsy of a melanoma to assess melanoma-specific survival and sentinel lymph node positivity. Objective: To assess the professional understanding, opinions, and clinical usage of the 31-GEP test by dermatologists. Methods: Data from 589 unique dermatologists were collected during 2 virtual, nation-wide dermatology conferences via an 18-question survey on practice demographics and their clinical use and opinion of the 31-GEP test. Results: Participants reported that integrating the 31-GEP test may benefit patients by increasing knowledge and understanding (72.5%), personalizing treatment options (58.8%), and easing uncertainty about the future (59.7%). Benefits of using the 31-GEP test included identifying true negative patients in high-risk populations (65.6%) as well as true positives in low-risk populations (70.6%).A majority of participants also noted that if a patient received a 31-GEP Class 2B result, they would escalate subsequent management even if the lesions were classified as T1 (61.4%) or AJCC8 Stage I (59.0%). 84.9% of participants were somewhat to very likely to use 31-GEP testing for patient management or recommend this test to a colleague. Limitations: Potential respondent-selection and recall bias. Conclusion: Dermatologists are increasingly integrating the 31-GEP test into their melanoma clinical management decisions. As the 31-GEP test becomes more prevalent in practice, patients may benefit from decreased anxiety and uncertainty from enhanced prognosis, decreased need for unwarranted procedures such as sentinel lymph node biopsy and optimized allocation of healthcare resources.
  • Considerations in the Management of Actinic Keratoses: The Importance of Adherence and Persistence to Therapy

    Marson, Justin; Del Rosso, James; Bhatia, Neal; Rigel, Darrell (National Society for Cutaneous Medicine, 2021-03-06)
    Background: Actinic keratosis (AK) is a pre-malignant lesion with a poorly defined risk of progression to invasive squamous cell carcinoma (SCC). AKs are also associated with increased future risk of invasive SCC. However, there are many barriers to therapy adherence that may affect long-term treatment efficacy. Objective: To review the current literature reporting known known factors of AK treatment non-adherence intrinsic to patient behavior and treatment regimens and re-examine how dermatologists can navigate these challenges. Methods: A Medline literature search was performed to identify existing evidence regarding barriers to adherence with AK treatment regimens intrinsic to patient behavior, patient counseling, and treatment regimens pertinent for review. Results & Discussion: Factors intrinsic to prescribed patient-applied therapy that can exacerbate non-adherence include: 1) length of treatment duration, 2) frequency of application, 3) complexity of treatment regimen, 4) duration and 5) severity of local skin reactions (LSR) and adverse reactions. Novel mechanisms of action that induce cellular apoptosis (as opposed to necrosis) via inhibition of tubulin polymerization and cell cycle arrest, may promote treatment regimen adherence and long-term outcomes. Dermatologists should also be conscious of how they counsel patients as insufficient counseling may also lead to poor adherence. Conclusion: Dermatologists must understand the value of shorter course therapies and their positive impact on adherence and be well-versed in the mechanisms, efficacy and adverse events associated with treatment options. By doing so, dermatologists may best counsel and educate patients and devise regimens that address individualized patient concerns.
  • Apremilast as an Off-Label Therapeutic Agent

    Marson, Justin; Lebwohl, Mark (National Society for Cutaneous Medicine, 2021-05-17)
    Objective: To review the literature regarding the efficacy and safety of off-label use of apremilast in combination therapies for psoriasis and psoriatic arthritis and for other currently off-label inflammatory dermatoses. Methods: The Medline database was queried for all relevant articles published between 2014 and 2021 using exploded MeSH terms and keywords pertaining to the following themes: off-label, combination therapy, biologics, biologic therapy, methotrexate, and systemic psoriasis therapy. The Boolean term “AND” was used to find the intersection of these themes with the term “apremilast.” Results: 8 case series and 6 case reports investigated the use of apremilast in combination therapy for psoriasis and psoriatic arthritis. Addition of apremilast improved PASI scores by 31.8-77.4% among case series and 80-100% among case reports with adverse effects primarily consisting of gastrointestinal symptoms. 5 randomized-control trials (RCT), 9 open-label trials, 18 case series, and 30 case reports investigated the use of apremilast for off-label dermatoses. In RCTs, apremilast showed potential efficacy for atopic dermatitis and hidradenitis suppurativa. Open-label trials found apremilast efficacious for atopic dermatitis, allergic contact dermatitis, chronic pruritus, cutaneous sarcoidosis, discoid lupus erythematosus, hidradenitis suppurativa, lichen planus, prurigo nodularis, rosacea, and vitiligo. Limitations: Small sample size and short follow up duration for available randomized-control and open-label trials. Current data from case series/reports potentially limits generalizability of findings. Conclusion: Apremilast's safety profile makes it a potential efficacious, non-biologic systemic agent for monotherapy and combination therapy for a wide range of inflammatory dermatoses.

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