Now showing items 1-20 of 12435

    • Novel antibacterial calcium phosphate nanocomposite with long-term ion recharge and re-release to inhibit caries

      Bhadila, Ghalia; Baras, Bashayer H.; Weir, Michael D.; Wang, Haohao; Melo, Mary Ann S.; Hack, Gary D.; Bai, Yuxing; Xu, Hockin H.K. (Nihon Shika Riko Gakkai/Japanese Society for Dental Materials and Devices, 2020-07-30)
      Short-term studies on calcium-phosphate (CaP) ion-rechargeable composites were reported. The long-term rechargeability is important but unknown. The objectives of this study were to investigate nanocomposite with strong antibacterial and ion-recharge capabilities containing dimethylaminododecyl methacrylate (DMAHDM) and nanoparticles of amorphous calcium phosphate (NACP), and evaluate long-term ion-recharge by testing for 12 cycles (taking 6 months to complete) for the first time. Three groups were tested: (1) Heliomolar control; (2) Resin+20%NACP+50%glass; (3) Resin+3%DMAHDM+20%NACP+50%glass. Biofilm acid and colony-forming units (CFU) were measured. Ion-recharge was tested for 12 cycles. NACP-DMAHDM composite reduced biofilm acid, and reduced CFU by 4 logs. High levels of ion releases were maintained throughout 12 cycles of recharge, maintaining steady-state releases without reduction in 6 months (p>0.1), representing long-term remineralization potential. Bioactive nanocomposite demonstrated long-term ion-rechargeability for the first time, showed remineralization and potent anti-biofilm functions, with promise for tooth restorations to combat caries.
    • Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation

      Li, Xiaofei; Zhao, Jing; Kasinath, Vivek; Uehara, Mayuko; Jiang, Liwei; Banouni, Naima; McGrath, Martina M; Ichimura, Takaharu; Fiorina, Paolo; Lemos, Dario R; et al. (American Society of Clinical Oncology, 2020-08-03)
      Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.
    • Emerging contact-killing antibacterial strategies for developing anti-biofilm dental polymeric restorative materials

      Mitwalli, Heba; Alsahafi, Rashed; Balhaddad, Abdulrahman A.; Weir, Michael D.; Xu, Hockin H.K.; Melo, Mary Anne S. (MDPI AG, 2020-07-30)
      Polymeric materials are the first choice for restoring tooth cavities, bonding tooth-colored fillings, sealing root canal systems, and many other dental restorative applications. However, polymeric materials are highly susceptible to bacterial attachment and colonization, leading to dental diseases. Many approaches have been investigated to minimize the formation of biofilms over polymeric restorative materials and at the tooth/material interfaces. Among them, contact-killing compounds have shown promising results to inhibit dental biofilms. Contact-killing compounds can be immobilized within the polymer structure, delivering a long-lasting effect with no leaching or release, thus providing advantages compared to release-based materials. This review discusses cutting-edge research on the development of contact-killing compounds in dental restorative materials to target oral pathogens. Contact-killing compounds in resin composite restorations, dental adhesives, root canal sealers, denture-based materials, and crown cements have all demonstrated promising antibacterial properties. Contact-killing restorative materials have been found to effectively inhibit the growth and activities of several oral pathogens related to dental caries, periodontal diseases, endodontic, and fungal infections. Further laboratory optimization and clinical trials using translational models are needed to confirm the clinical applicability of this new generation of contact-killing dental restorative materials.
    • Circulating microparticle concentrations across acute and chronic cardiovascular disease conditions

      Landers-Ramos, Rian Q; Addison, Odessa A; Beamer, Brock; Katzel, Leslie I; Blumenthal, Jacob B; Robinson, Shawn; Hagberg, James M; Prior, Steven J (Wiley-Blackwell, 2020-08)
      Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies. PURPOSE: To quantify plasma concentrations of CD31+/CD42b-, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non-ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60-75 years old. METHODS: CD31+/CD42b-, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed. RESULTS: Concentrations of CD31+/CD42b- MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03). CONCLUSIONS: Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b- MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations. © 2020 The Authors.
    • Convalescent serum therapy for COVID-19: A 19th century remedy for a 21st century disease

      Montelongo-Jauregui, Daniel; Vila, Taissa; Sultan, Ahmed S.; Jabra-Rizk, Mary Ann (Public Library of Science (PLoS), 2020-08-12)
    • Home Exercise Interventions in Frail Older Adults

      Stookey, Alyssa D.; Katzel, Leslie I. (Springer Nature, 2020-08-05)
      Purpose of Review: Frailty is characterized by decreased physiological reserve and increased risk of falls, disability, hospitalization, and mortality. Frail older adults may benefit from exercise interventions targeting their multiple problems and functional deficits; however, most research focuses on center-based interventions, which may present accessibility challenges for frail older adults. Therefore, the purpose of this review is to summarize the most recently published home-based exercise interventions for frail older adults living at home. Recent Findings: Eight manuscripts met inclusion criteria. Research interventions consisted of a variety of modes (strength, strength/nutrition, strength/flexibility/balance/endurance), duration (12 weeks to 6 months), frequency (2–7 days/week), and delivery methods (volunteer-led, videos on a tablet, manuals/brochures). Investigators examined the effects of home-based exercise on a variety of outcomes to include feasibility, frailty status, physical performance, lean body mass, skeletal muscle mass, other physiological outcomes, mental health, nutritional status, and incidence of falls in frail. Summary: This review demonstrates the feasibility and effectiveness of home-based exercise interventions to improve frailty, functional performance, nutritional status, and incidence of falls in frail older adults. However, the limited literature available provides conflicting reports regarding benefits for mental health outcomes and no evidence of a beneficial effect on skeletal muscle or lean mass. Future research is needed to shed light on the optimal components of home exercise programs most important for maximizing benefits for frail older adults, as well as the most effective delivery method. © 2020, The Author(s).
    • A phase 2B randomised trial of hyperbaric oxygen therapy for ulcerative colitis patients hospitalised for moderate to severe flares

      Dulai, Parambir S.; Raffals, Laura E.; Hudesman, David; Chiorean, Michael; Cross, Raymond; Ahmed, Tasneem; Winter, Michael; Chang, Shannon; Fudman, David; Sadler, Charlotte; et al. (Wiley-Blackwell, 2020-08-03)
      Background: Hyperbaric oxygen has been reported to improve disease activity in hospitalised ulcerative colitis (UC) patients. Aim: To evaluate dosing strategies with hyperbaric oxygen for hospitalised UC patients. Methods: We enrolled UC patients hospitalised for acute flares (Mayo score 6-12). Initially, all patients received 3 days of hyperbaric oxygen at 2.4 atmospheres (90 minutes with two air breaks) in addition to intravenous steroids. Day 3 responders (reduction of partial Mayo score ≥ 2 points and rectal bleeding score ≥ 1 point) were randomised to receive a total of 5 days vs 3 days of hyperbaric oxygen. Results: We treated 20 patients with hyperbaric oxygen (75% prior biologic failure). Day 3 response was achieved in 55% (n = 11/20), with significant reductions in stool frequency, rectal bleeding and CRP (P < 0.01). A more significant reduction in disease activity was observed with 5 days vs 3 days of hyperbaric oxygen (P = 0.03). Infliximab or colectomy was required in only three patients (15%) despite a predicted probability of 80% for second-line therapy. Day 3 hyperbaric oxygen responders were less likely to require re-hospitalisation or colectomy by 3 months vs non-responders (0% vs 66%, P = 0.002). No treatment-related adverse events were observed. Conclusion: Hyperbaric oxygen appears to be effective for optimising response to intravenous steroids in UC patients hospitalised for acute flares, with low rates of re-hospitalisation or colectomy at 3 months. An optimal clinical response is achieved with 5 days of hyperbaric oxygen. Larger phase 3 trials are needed to confirm efficacy and obtain labelled approval.
    • Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial

      Haac, Bryce E; O'Hara, Nathan N; Manson, Theodore T; Slobogean, Gerard P; Castillo, Renan C; O'Toole, Robert V; Stein, Deborah M (Public Library of Science, 2020-08-03)
      BACKGROUND: Emerging evidence suggests aspirin may be an effective venous thromboembolism (VTE) prophylaxis for orthopaedic trauma patients, with fewer bleeding complications. We used a patient-centered weighted composite outcome to globally evaluate aspirin versus low-molecular-weight heparin (LMWH) for VTE prevention in fracture patients. METHODS: We conducted an open-label randomized clinical trial of adult patients admitted to an academic trauma center with an operative extremity fracture, or a pelvis or acetabular fracture. Patients were randomized to receive LMWH (enoxaparin 30-mg) twice daily (n = 164) or aspirin 81-mg twice daily (n = 165). The primary outcome was a composite endpoint of bleeding complications, deep surgical site infection, deep vein thrombosis, pulmonary embolism, and death within 90 days of injury. A Global Rank test and weighted time to event analysis were used to determine the probability of treatment superiority for LMWH, given a 9% patient preference margin for oral administration over skin injections. RESULTS: Overall, 18 different combinations of outcomes were experienced by patients in the study. Ninety-nine patients in the aspirin group (59.9%) and 98 patients in the LMWH group (59.4%) were event-free within 90 days of injury. Using a Global Rank test, the LMWH had a 50.4% (95% CI, 47.7-53.2%, p = 0.73) probability of treatment superiority over aspirin. In the time to event analysis, LMWH had a 60.5% probability of treatment superiority over aspirin with considerable uncertainty (95% CI, 24.3-88.0%, p = 0.59). CONCLUSION: The findings of the Global Rank test suggest no evidence of superiority between LMWH or aspirin for VTE prevention in fracture patients. LMWH demonstrated a 60.5% VTE prevention benefit in the weighted time to event analysis. However, this difference did not reach statistical significance and was similar to the elicited patient preferences for aspirin.
    • Early Symptom Improvement as a Predictor of Antidepressant Response in Children and Adolescents Diagnosed with Depression: Translating Evidence from Randomized Controlled Trials to Community Practice

      Spence, O'Mareen; dosReis, Susan (2020)
      Statement of the Problem: A common problem among children and adolescents diagnosed with depression who receive care in community settings is that antidepressant regimen changes such as psychotropic augmentation may occur soon after starting treatment. This raises the question as to whether such changes are implemented among youth who would otherwise respond to the antidepressant. Thus, the overarching objectives of this dissertation were to 1) distinguish early in treatment children and adolescents who are likely to respond, and 2) empirically evaluate the association between predicted response and psychotropic augmentation or switching in real world settings. Summary of Methods: Using randomized clinical trial (RCT) data, this research applied a Bayesian approach to predict the likelihood of initial (12 week) and sustained (18 week) response to treatment as a function of early changes in depressive symptoms (i.e. mood, somatic, subjective and behavioral) and other demographic and clinical factors. An innovative application of combined sample multiple imputations (CSMI) was used to estimate the 12-week predicted probability of response among commercially insured adolescents who received care in real-world settings. Each adolescent received a probability of treatment response, which was then used to compare the odds of psychotropic augmentation or switch. Results: Early changes in mood and somatic symptoms within the first six weeks of treatment are primary predictors of initial (at 12 weeks) and sustained (at 18 weeks) response to an antidepressant. Baseline depression severity is an important prognostic factor for initial response, and additional, though minimal improvement, in somatic symptoms from weeks 6 to 12 is indicative of sustained response. In a highly selected cohort of adolescents receiving care in community settings, an augmentation or switch occurred similarly among adolescents with a high versus low likelihood of responding to fluoxetine. Conclusion: The results suggest that other factors beyond expected antidepressant response (or lack thereof) might influence current treatment practices. Our findings have clinical and public health implications that support measurement-based care in pediatric depression. Our application of CSMI highlights several key areas of consideration for future pharmacoepidemiologic research aimed at translating RCT evidence to real world data to better understand clinical practices patterns.
    • goFOOD<TM>: An artificial intelligence system for dietary assessment

      Lu, Ya; Stathopoulou, Thomai; Vasiloglou, Maria F.; Pinault, Lillian F.; Kiley, Colleen; Spanakis, Elias K.; Mougiakakou, Stavroula (MDPI AG, 2020-08-01)
      Accurate estimation of nutritional information may lead to healthier diets and better clinical outcomes. We propose a dietary assessment system based on artificial intelligence (AI), named goFOOD™. The system can estimate the calorie and macronutrient content of a meal, on the sole basis of food images captured by a smartphone. goFOOD™ requires an input of two meal images or a short video. For conventional single-camera smartphones, the images must be captured from two different viewing angles; smartphones equipped with two rear cameras require only a single press of the shutter button. The deep neural networks are used to process the two images and implements food detection, segmentation and recognition, while a 3D reconstruction algorithm estimates the food’s volume. Each meal’s calorie and macronutrient content is calculated from the food category, volume and the nutrient database. goFOOD™ supports 319 fine-grained food categories, and has been validated on two multimedia databases that contain non-standardized and fast food meals. The experimental results demonstrate that goFOOD™ performed better than experienced dietitians on the non-standardized meal database, and was comparable to them on the fast food database. goFOOD™ provides a simple and efficient solution to the end-user for dietary assessment. © 2020 by the authors.
    • Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis

      Brunwasser, Steven M.; Snyder, Brittney M.; Driscoll, Amanda J.; Fell, Deshayne B.; Savitz, David A.; Feikin, Daniel R.; Skidmore, Becky; Bhat, Niranjan; Bont, Louis J.; Dupont, William D.; et al. (Elsevier Ltd., 2020-08-01)
      Background: Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines. Methods: We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the loge odds ratio (loge OR) scale. Findings: From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR+ 2·45, 95% CI 1·23–4·88) compared with those that did not (4·17, 2·36–7·37), a significant difference (b 0·53, 95% CI 0·04–1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR+ 1·21, 95% CI 0·73–1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data. Interpretation: Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s).
    • Tenacious Endemic Typhoid Fever in Samoa

      Sikorski, Michael J; Desai, Sachin N; Tupua, Siaosi; Thomsen, Robert E; Han, Jane; Rambocus, Savitra; Nimarota-Brown, Susana; Punimata, Linatupu; Tusitala, Salesa; Sialeipata, Michelle; et al. (Oxford University Press, 2020-07-29)
      BACKGROUND: Typhoid fever has been endemic on the island nation of Samoa (2016 population, 195 979) since the 1960s and has persisted through 2019, despite economic development and improvements in water supply and sanitation. METHODS: Salmonella enterica serovar Typhi isolates from the 2 hospitals with blood culture capability and matched patient demographic and clinical data from January 2008 through December 2019 were analyzed. Denominators to calculate incidence by island, region, and district came from 2011 and 2016 censuses and from 2017-2019 projections from Samoa's Bureau of Statistics. Data were analyzed to describe typhoid case burden and incidence from 2008 to 2019 by time, place, and person. RESULTS: In sum, 53-193 blood culture-confirmed typhoid cases occurred annually from 2008 to 2019, without apparent seasonality. Typhoid incidence was low among children age < 48 months (17.6-27.8/105), rose progressively in ages 5-9 years (54.0/105), 10-19 years (60.7-63.4/105), and 20-34 years (61.0-79.3/105), and then tapered off; 93.6% of cases occurred among Samoans < 50 years of age. Most typhoid cases and the highest incidence occurred in Northwest Upolu, but Apia Urban Area (served by treated water supplies) also exhibited moderate incidence. The proportion of cases from short-cycle versus long-cycle transmission is unknown. Samoan S. Typhi are pansusceptible to traditional first-line antibiotics. Nevertheless, enhanced surveillance in 2019 detected 4 (2.9%) deaths among 140 cases. CONCLUSIONS: Typhoid has been endemic in Samoa in the period 2008-2019. Interventions, including mass vaccination with a Vi-conjugate vaccine coadministered with measles vaccine are planned. © The Author(s) 2020.
    • Early Insights From Clinical Trials of Typhoid Conjugate Vaccine

      Neuzil, Kathleen M; Basnyat, Buddha; Clemens, John D; Gordon, Melita A; Patel, Priyanka D; Pollard, Andrew J; Shakya, Mila; Qadri, Firdausi (Oxford University Press, 2020-07-29)
      Clinical trials of typhoid conjugate vaccine (TCV) are ongoing in 4 countries. Early data confirm safety, tolerability, and immunogenicity of typhoid conjugate vaccine, and early efficacy results are promising. These data support World Health Organization recommendations and planned country introductions. Forthcoming trial data will continue to inform programmatic use of typhoid conjugate vaccine. © The Author(s) 2020.
    • Contribution of central sensitization to stress-induced spreading hyperalgesia in rats with orofacial inflammation

      Li, Jia-Heng; Yang, Jia-Le; Wei, Si-Qi; Li, Zhuo-Lin; Collins, Anna A; Zou, Min; Wei, Feng; Cao, Dong-Yuan (Springer Nature, 2020-07-28)
      Temporomandibular disorder (TMD) is commonly comorbid with fibromyalgia syndrome (FMS). The incidence of these pain conditions is prevalent in women and prone to mental stress. Chronic pain symptoms in patients with FMS and myofascial TMD (mTMD) are severe and debilitating. In the present study, we developed a new animal model to mimic the comorbidity of TMD and FMS. In ovariectomized female rats, repeated forced swim (FS) stress induced mechanical allodynia and thermal hyperalgesia in the hindpaws of the 17β-estradiol (E2) treated rats with orofacial inflammation. Subcutaneous injection of E2, injection of complete Freund's adjuvant (CFA) into masseter muscles or FS alone did not induce somatic hyperalgesia. We also found that the somatic hyperalgesia was accompanied by upregulation of GluN1 receptor and serotonin (5-hydroxytryptamine, 5-HT)3A receptor expression in the dorsal horn of spinal cord at L4-L5 segments. Intrathecal injection of N-methyl-D-aspartic acid receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (APV) or 5-HT3 receptor antagonist Y-25130 blocked stress-induced wide-spreading hyperalgesia. These results suggest that NMDAR-dependent central sensitization in the spinal dorsal horn and 5-HT-dependent descending facilitation contribute to the development of wide-spreading hyperalgesia in this comorbid pain model.
    • Abnormalities in Brain and Muscle Microstructure and Neurochemistry of the DMD Rat Measured by in vivo Diffusion Tensor Imaging and High Resolution Localized 1H MRS

      Xu, Su; Tang, Shiyu; Li, Xin; Iyer, Shama R.; Lovering, Richard M. (Frontiers Media S.A., 2020-07-14)
      Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by the lack of dystrophin with progressive degeneration of skeletal muscles. Most studies regarding DMD understandably focus on muscle, but dystrophin is also expressed in the central nervous system, potentially resulting in cognitive and behavioral changes. Animal models are being used for developing more comprehensive neuromonitoring protocols and clinical image acquisition procedures. The recently developed DMD rat is an animal model that parallels the progressive muscle wasting seen in DMD. Here, we studied the brain and temporalis muscle structure and neurochemistry of wild type (WT) and dystrophic (DMD) rats using magnetic resonance imaging and spectroscopy. Both structural and neurochemistry alterations were observed in the DMD rat brain and the temporalis muscle. There was a decrease in absolute brain volume (WT = 1579 mm3; DMD = 1501 mm3; p = 0.039, Cohen’s d = 1.867), but not normalized (WT = 4.27; DMD = 4.02; p = 0.306) brain volume. Diffusion tensor imaging (DTI) revealed structural alterations in the DMD temporalis muscle, with increased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). In the DMD rat thalamus, DTI revealed an increase in fractional anisotropy (FA) and a decrease in RD. Smaller normalized brain volume correlated to severity of muscle dystrophy (r = −0.975). Neurochemical changes in the DMD rat brain included increased GABA and NAA in the prefrontal cortex, and GABA in the hippocampus. Such findings could indicate disturbed motor and sensory signaling, resulting in a dysfunctional GABAergic neurotransmission, and an unstable osmoregulation in the dystrophin-null brain. © Copyright © 2020 Xu, Tang, Li, Iyer and Lovering.
    • The implications of silent transmission for the control of COVID-19 outbreaks

      Moghadas, Seyed M; Fitzpatrick, Meagan C; Sah, Pratha; Pandey, Abhishek; Shoukat, Affan; Singer, Burton H; Galvani, Alison P (National Academy of Sciences, 2020-07-28)
      Since the emergence of coronavirus disease 2019 (COVID-19), unprecedented movement restrictions and social distancing measures have been implemented worldwide. The socioeconomic repercussions have fueled calls to lift these measures. In the absence of population-wide restrictions, isolation of infected individuals is key to curtailing transmission. However, the effectiveness of symptom-based isolation in preventing a resurgence depends on the extent of presymptomatic and asymptomatic transmission. We evaluate the contribution of presymptomatic and asymptomatic transmission based on recent individual-level data regarding infectiousness prior to symptom onset and the asymptomatic proportion among all infections. We found that the majority of incidences may be attributable to silent transmission from a combination of the presymptomatic stage and asymptomatic infections. Consequently, even if all symptomatic cases are isolated, a vast outbreak may nonetheless unfold. We further quantified the effect of isolating silent infections in addition to symptomatic cases, finding that over one-third of silent infections must be isolated to suppress a future outbreak below 1% of the population. Our results indicate that symptom-based isolation must be supplemented by rapid contact tracing and testing that identifies asymptomatic and presymptomatic cases, in order to safely lift current restrictions and minimize the risk of resurgence.
    • Surveillance for Invasive Salmonella Disease in Bamako, Mali, From 2002 to 2018

      Still, William L; Tapia, Milagritos D; Tennant, Sharon M; Sylla, Mamadou; Touré, Aliou; Badji, Henry; Keita, Adama Mamby; Sow, Samba O; Levine, Myron M; Kotloff, Karen L (Oxford University Press, 2020-07-09)
      BACKGROUND: Salmonella enterica bloodstream infections are an important cause of childhood morbidity and mortality, including in Mali. We report 17 years of surveillance for nontyphoidal and typhoidal S. enterica infections among inpatients and outpatients at l'Hôpital Gabriel Touré, the main source of pediatric tertiary care in Bamako, Mali. METHODS: Between June 2002 and December 2018, a blood culture was collected from 54 748 children aged ≤15 years with fever and/or suspected invasive bacterial infection who provided consent (38 152 inpatients, 16 596 outpatients). Bacterial pathogens were identified using standard microbiological techniques and serovars of S. enterica were determined by PCR and/or agglutination with antisera. RESULTS: Nontyphoidal Salmonella (NTS) was identified in 671 enrolled inpatients (1.8% of all enrolled inpatients, 13.8% of enrolled inpatients with a positive culture). S. Enteritidis, the most common NTS serovar, accounted for 38.5% of all NTS isolates (n = 258), followed by S. Typhimurium (31.7%, n = 213). The median (SD) age of children with a culture positive for NTS was 1.8 (3) years. Overall case fatality was 20.9%. An additional 138 inpatients (0.4%) had a positive culture for typhoidal Salmonella. NTS was identified in 11 outpatients (0.07%), while typhoidal Salmonella was found in 49 outpatients (0.3%). The annual incidence of invasive NTS disease decreased over the study period, but case fatality remained high. CONCLUSIONS: Although incidence decreased, NTS remained a major cause of invasive bacterial infection and mortality among hospitalized children in Bamako, while typhoidal Salmonella was uncommon. Because 87% of NTS belonged to only 4 serovars, a multivalent vaccine may be an effective strategy to reduce the burden and mortality of invasive NTS. © The Author(s) 2020.
    • A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression

      Park, Lawrence T; Kadriu, Bashkim; Gould, Todd D; Zanos, Panos; Greenstein, Deanna; Evans, Jennifer W; Yuan, Peixiong; Farmer, Cristan A; Oppenheimer, Mark; George, Jomy M; et al. (Oxford University Press, 2020-03-31)
      BACKGROUND: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. METHODS: After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. RESULTS: Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. CONCLUSIONS: In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.ClinicalTrials.gov identifier: NCT02484456.
    • The pangenome: A data-driven discovery in biology

      Medini, Duccio; Donati, Claudio; Rappuoli, Rino; Tettelin, Hervé (Springer Nature, 2020-06-22)
      An early example of Big data in biology: how a mathematical model, developed to address a practical question in vaccinology, transformed established concepts, opening biology to the “unbounded.”
    • A Model for Assessing Professional Association Engagement

      Gorman, Emily; Jackson, K. D.; Harrold, M.W.; Mercer, S.L.; Metcalf, M.; Lebovitz, Lisa; Tucker, Shannon R.; Block, K.F.; Franzini, R.; Coop, Andrew (2020)
      Assessing member engagement with a professional association is critical in determining the success of programs such as the AACP New Investigator Award (NIA), because engagement leads to organizational growth and is key to long term sustainability. A review of the literature indicated that many organizations are focused on increasing engagement, but there are few quantifications of engagement to be used to measures success of initiatives. Use of online communication tools such as AACP Connect can be quantified, and are often used as a proxy for engagement, but the literature is clear that the majority of individuals may be avid readers, but do not post. The authors searched peer-reviewed and organizational literature for published models evaluating organizational engagement to create a modified scale to quantify engagement following the NIA. The American Bar Association published an article assessing engagement of its members with five tiers, explaining the tiers as a continuum. Although presented by ABA as a continuum, this approach was seen by the authors as an approach to measure the depth of engagement.