Recent Submissions

  • Rotavirus disease burden pre-vaccine introduction in young children in Rural Southern Mozambique, an area of high HIV prevalence.

    Acácio, Sozinho; Nhampossa, Tacilta; Quintò, Llorenç; Vubil, Delfino; Garrine, Marcelino; Bassat, Quique; Farag, Tamer; Panchalingam, Sandra; Nataro, James P; Kotloff, Karen L; et al. (Public Library of Science, 2021-04-08)
    Background: Rotavirus vaccines have been adopted in African countries since 2009, including Mozambique (2015). Disease burden data are needed to evaluate the impact of rotavirus vaccine. We report the burden of rotavirus-associated diarrhea in Mozambique from the Global Enteric Multicenter Study (GEMS) before vaccine introduction. Methods: A case-control study (GEMS), was conducted in Manhiça district, recruiting children aged 0-59 months with moderate-to-severe diarrhea (MSD) and less-severe-diarrhea (LSD) between December 2007 and November 2012; including 1-3 matched (age, sex and neighborhood) healthy community controls. Clinical and epidemiological data and stool samples (for laboratory investigation) were collected. Association of rotavirus with MSD or LSD was determined by conditional logistic regression and adjusted attributable fractions (AF) calculated, and risk factors for rotavirus diarrhea assessed. Results: Overall 915 cases and 1,977 controls for MSD, and 431 cases and 430 controls for LSD were enrolled. Rotavirus positivity was 44% (217/495) for cases and 15% (160/1046) of controls, with AF = 34.9% (95% CI: 32.85-37.06) and adjusted Odds Ratio (aOR) of 6.4 p< 0.0001 in infants with MSD compared to 30% (46/155) in cases and 14% (22/154) in controls yielding AF = 18.7%, (95% CI: 12.02-25.39) and aOR = 2.8, p = 0.0011 in infants with LSD. The proportion of children with rotavirus was 32% (21/66) among HIV-positive children and 23% (128/566) among HIV-negative ones for MSD. Presence of animals in the compound (OR = 1.9; p = 0.0151) and giving stored water to the child (OR = 2.0, p = 0.0483) were risk factors for MSD; while animals in the compound (OR = 2.37, p = 0.007); not having routine access to water on a daily basis (OR = 1.53, p = 0.015) and washing hands before cooking (OR = 1.76, p = 0.0197) were risk factors for LSD. Conclusion: The implementation of vaccination against rotavirus may likely result in a significant reduction of rotavirus-associated diarrhea, suggesting the need for monitoring of vaccine impact.
  • Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

    Yu, Ruofan; Cao, Xiaohua; Sun, Luyang; Zhu, Jun-Yi; Wasko, Brian M; Liu, Wei; Crutcher, Emeline; Liu, Haiying; Jo, Myeong Chan; Qin, Lidong; et al. (Nature Publishing Group, 2021-03-31)
    Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencing-Based Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. We find that, in addition to longer lifespan, disruption of HDA results in resistance to DNA damage and osmotic stresses. We show that these effects are due to increased promoter H3K18 acetylation and transcriptional activation in the trehalose metabolic pathway in the absence of HDA. Furthermore, we determine that the longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex known to interact with HDA and coordinate transcriptional repression. Silencing the HDA homologs in C. elegans and Drosophila increases their lifespan and delays aging-associated physical declines in adult flies. Hence, we demonstrate that this HDAC controls an evolutionarily conserved longevity pathway.
  • Implantable cardiac devices in geriatric patients: a primer for primary and geriatric physicians

    Wani, Farah; Amir, Rawan; Aljadah, Michael; Albosta, Michael; Guidi, Jean Claude; Singh, Jagmeet; Kanjwal, Khalil; Kichloo, Asim (MedReviews, 2021-03-30)
    In the next 20 years, the percentage of people older than 65 years of age in the United States is expected to double. Heart disease is the leading cause of mortality in developed nations, including the United States. Due to the increased incidence of cardiac disease in elderly patients, the need for special treatment considerations, including cardiac devices, may be necessary to reduce morbidity and mortality in this patient population. The purpose of this review is to provide a primer of the common cardiac devices used in the management of cardiac disorders in the geriatric patient population. In order to do this, we have performed a literature review for articles related to cardiac devices published between 2000 and 2020, in addition to reviewing guidelines and recommendations from relevant professional societies. We provide readers with an overview of several cardiac devices including implantable loop recorders, pacemakers, cardiac resynchronization therapy, automated implantable cardiac defibrillators, watchman devices, and ventricular assist devices. Indications, contraindications, clinical trial data, and general considerations in the geriatric population were included. Due to the aging population and increased incidence of cardiac disease, clinicians should be aware of the indications and contraindications of cardiac device therapy in the management of various cardiac conditions that afflict the geriatric population. © 2021 The Authors.
  • Perceptions of Resident Autonomy in Internal Medicine, Pediatrics, and Internal Medicine-Pediatrics

    Mieczkowski, Alexandra E; Gonzaga, Alda Maria R; Kraemer, Kevin; Habicht, Robert; Friedland, Allen R; Rubio, Doris; Van Deusen, Reed (Springer Nature, 2021-03-10)
    Of 489 eligible respondents, 215 (44%) responded. Internal medicine-pediatrics residents were more likely than categorical pediatrics residents and pediatrics faculty to disagree that they received an appropriate level of autonomy while on inpatient pediatrics general wards (mean = 2.7 relative to 4.0 and 4.3, categorical residents and faculty; 5-point Likert scale; P < .001). On a 5-point Likert scale, the internal medicine-pediatrics residents were more likely to agree that they received too much oversight on pediatrics general ward rotations (mean, 3.9) compared to internal medicine general ward rotations (mean, 1.9) with a P-value between rotations of <.001. Combined internal medicine-pediatrics perceptions of too much oversight while on pediatric general ward rotations were significantly different from their categorical pediatrics peers (pediatrics mean 2.0, P < .001).
  • Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition.

    Li, Shuaizhang; Zhao, Jinghua; Huang, Ruili; Travers, Jameson; Klumpp-Thomas, Carleen; Yu, Wenbo; MacKerell, Alexander D; Sakamuru, Srilatha; Ooka, Masato; Xue, Fengtian; et al. (National Institute of Environmental Health Sciences, 2021-04-12)
    Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents). Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models. Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively. Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds. Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993.
  • Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review

    Wieland, L Susan; Piechotta, Vanessa; Feinberg, Termeh; Ludeman, Emilie; Hutton, Brian; Kanji, Salmaan; Seely, Dugald; Garritty, Chantelle (Springer Nature, 2021-04-07)
    Background: Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines. Methods: We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness. Results: We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time. Conclusions: Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.
  • Long-term Risk of Hypertension After Surgical Repair of Congenital Heart Disease in Children

    Greenberg, Jason H; McArthur, Eric; Thiessen-Philbrook, Heather; Zappitelli, Michael; Wald, Ron; Kaushal, Sunjay; Ng, Derek K; Everett, Allen D; Chanchlani, Rahul; Garg, Amit X; et al. (American Medical Association, 2021-04-08)
    IMPORTANCE: The long-term risk of hypertension in children after surgery for congenital heart disease (CHD) is unclear. OBJECTIVE: To assess the incidence of hypertension after cardiac surgery in children with CHD. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective matched cohort study was conducted in Ontario, Canada, using administrative databases. A total of 3600 children with surgical repair of CHD were matched to 10 children (n = 36 000) from the general population without CHD on age, sex, index date, rurality, and neighborhood income. MAIN OUTCOMES AND MEASURES: Diagnosis of hypertension over a median follow-up time of 9.8 years (interquartile range, 6.8-12.9 years) after surgery. The last follow-up was March 31, 2019. RESULTS: Overall, in 3600 children with surgical repair of CHD, the median age at first surgery was 150 days (interquartile range, 40-252 days) and 2005 (55.7%) were boys. During follow-up, 445 (12.4%) children with surgical repair of CHD developed hypertension compared with 398 (1.1%) in the matched control group. The incidence rate of hypertension in children who received surgery for CHD was 141.3 (95% CI, 128.8-155.1) per 10 000 person-years compared with children in the matched control group, who had a rate of 11.1 (95% CI, 10.1-12.3) per 10 000 person-years. The risk of hypertension was higher in children with index surgical dates at an age of less 150 days compared with those who had surgical dates at an age of 150 days or older (P = .006 for interaction). The risk of hypertension was increased in children with more complex surgery, particularly children with hypoplastic left heart syndrome (49 of 140 [35.0%]), and in children who received dialysis (22 of 126 [17.5%]; hazard ratio, 1.67; 95% CI, 1.09-2.56) during the index cardiac surgery hospitalization. CONCLUSIONS AND RELEVANCE: The incidence of long-term hypertension in this study was 12 times higher in children with surgical repair of CHD compared with children in the matched control group. The findings suggest that interventions aimed at reducing the long-term risk of hypertension after cardiac surgery in this population are needed.
  • Systemic administration of a β2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity

    Arora, Vipin; Morado-Urbina, Carlos Eduardo; Gwak, Young S; Parker, Renee A; Kittel, Carol A; Munoz-Islas, Enriqueta; Miguel Jimenez-Andrade, Juan; Romero-Sandoval, E Alfonso; Eisenach, James C; Peters, Christopher M (SAGE Publications Inc., 2021-04-08)
    Beta 2 adrenergic receptor (β2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of β2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the β2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of β2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined β2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of β2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of β2-AR agonists to models of surgical injury.
  • LTβR Signaling Controls Lymphatic Migration of Immune Cells

    Piao, Wenji; Kasinath, Vivek; Saxena, Vikas; Lakhan, Ram; Iyyathurai, Jegan; Bromberg, Jonathan S (MDPI AG, 2021-03-29)
    The pleiotropic functions of lymphotoxin (LT)β receptor (LTβR) signaling are linked to the control of secondary lymphoid organ development and structural maintenance, inflammatory or autoimmune disorders, and carcinogenesis. Recently, LTβR signaling in endothelial cells has been revealed to regulate immune cell migration. Signaling through LTβR is comprised of both the canonical and non-canonical-nuclear factor κB (NF-κB) pathways, which induce chemokines, cytokines, and cell adhesion molecules. Here, we focus on the novel functions of LTβR signaling in lymphatic endothelial cells for migration of regulatory T cells (Tregs), and specific targeting of LTβR signaling for potential therapeutics in transplantation and cancer patient survival.
  • Bioresorbable stent to manage congenital heart defects in children

    Wright, Jamie; Nguyen, Annie; D'Souza, Nandika; Forbess, Joseph M.; Nugent, Alan; Reddy, Surendranath R. Veeram; Jaquiss, Robert; Welch, Tré Raymond (Elsevier B.V., 2021-03-19)
    Intravascular stents for pediatric patients that degrade without inhibiting vessel growth remain a clinical challenge. Here, poly(L-lactide) fibers (DH-BDS) at two thicknesses, 250 µm and 300 µm, were assembled into large, pediatric-sized stents (Ø10 - Ø20 mm). Fibers were characterized mechanically and thermally, then stent mechanical properties were compared to metal controls, while mass loss and degradation kinetics modeling estimated total stent degradation time. Thicker fibers displayed lower stiffness (1969 ± 44 vs 2126 ± 37 MPa) and yield stress (117 ± 12 vs 137 ± 5 MPa) than thinner counterparts, but exhibited similar fail strength (478 ± 28 vs 476 ± 16 MPa) at higher strains (47 ± 2 vs 44 ± 2%). Stents all exhibited crystallinity between 51.3 – 54.4% and fiber glass transition temperatures of 88.6 ± 0.5°C and 84.6 ± 0.5°C were well above physiological ranges. Radial strength (0.31 ± 0.01 - 0.34 ± 0.02 N/mm) in thinner stents was similar to metal stents (0.24 – 0.41 N/mm) up to Ø14 mm with no foreshortening and thicker coils granted comparable radial strength (0.32 ± 0.02 - 0.34 ± 0.02 N/mm) in stents larger than Ø14 mm. Both 10 mm (1.17 ± 0.02 % and 0.86 ± 0.1 %) and 12 mm (1.1 ± 0.03% and 0.89 ± 0.1%) stents exhibited minimal weight loss over one year. Degradation kinetics models predicted full stent degradation within 2.8 - 4.5 years depending on thickness. DH-BDS exhibiting hoop strength similar to metal stents and demonstrating minimal degradation and strength loss over the first year before completely disappearing within 3 to 4.5 years show promise as a pediatric interventional alternative to current strategies.
  • Minimizing the impact of the triple burden of COVID-19, tuberculosis and HIV on health services in sub-Saharan Africa

    Nachega, Jean B; Kapata, Nathan; Sam-Agudu, Nadia A; Decloedt, Eric H; Katoto, Patrick D M C; Nagu, Tumaini; Mwaba, Peter; Yeboah-Manu, Dorothy; Chanda-Kapata, Pascalina; Ntoumi, Francine; et al. (Elsevier B.V., 2021-03-20)
    In this perspective, we discuss the impact of COVID-19 on tuberculosis (TB)/HIV health services and approaches to mitigating the growing burden of these three colliding epidemics in sub-Saharan Africa (SSA). SSA countries bear significantly high proportions of TB and HIV cases reported worldwide, compared to countries in the West. Whilst COVID-19 epidemiology appears to vary across Africa, most countries in this region have reported relatively lower-case counts compared to the West. Nevertheless, the COVID-19 pandemic has added an additional burden to already overstretched health systems in SSA, which, among other things, have been focused on the longstanding dual epidemics of TB and HIV. As with these dual epidemics, inadequate resources and poor case identification and reporting may be contributing to underestimations of the COVID-19 case burden in SSA. Modelling studies predict that the pandemic-related disruptions in TB and HIV services will result in significant increases in associated morbidity and mortality over the next five years. Furthermore, limited empirical evidence suggests that SARS-CoV-2 coinfections with TB and HIV are associated with increased mortality risk in SSA. However, predictive models require a better evidence-base to accurately define the impact of COVID-19, not only on communicable diseases such as TB and HIV, but on non-communicable disease comorbidities. Further research is needed to assess morbidity and mortality data among both adults and children across the African continent, paying attention to geographic disparities, as well as the clinical and socio-economic determinants of COVID-19 in the setting of TB and/or HIV.
  • Spinal cord injury in the setting of traumatic thoracolumbar fracture is not reliably associated with increased risk of associated intra-abdominal injury following blunt trauma: An analysis of a National Trauma Registry database

    Zilbermints, Veacheslav; Hershkovitz, Yehuda; Peleg, Kobi; DuBose, Joseph J.; Givon, Adi; Aranovich, David; Dudkiewicz, Mickey; Kessel, Boris (Elsevier B.V., 2021-03-26)
    Purpose: There is a common opinion that spine fractures usually reflect the substantial impact of injuries and therefore may be used as a marker of significant associated injuries, specifically for intra-abdominal injury (IAI). The impact of concomitant spinal cord injury (SCI) with the risk of associated IAI has not been well clarified. The aim of this study was to evaluate the incidence and severity of IAIs in patients suffering from spine fractures with or without SCI. Methods: A retrospective cohort study using the Israeli National Trauma Registry was conducted. Patients with thoracic, lumbar and thoracolumbar fractures resulting from blunt mechanisms of injury from 1997 to 2018 were examined, comparing the incidence, severity and mortality of IAIs in patients with or without SCI. The collected variables included age, gender, mechanism of injury, incidence and severity of the concomitant IAIs and pelvic fractures, abbreviated injury scale, injury severity score, and mortality. Statistical analysis was performed using GraphPad InStat ® Version 3.10, with Chi-square test for independence and two sided Fisher's exact probability test. Results: Review of the Israeli National Trauma Database revealed a total of 16,878 patients with spinal fractures. Combined thoracic and lumbar fractures were observed in 7.5% of patients; isolated thoracic fractures in 29.4% and isolated lumbar fractures in 63.0%. The incidence of concomitant SCI was found in 4.95% (63/1272), 7.65% (380/4967) and 2.5% (266/10639) of these patients, respectively. The overall mortality was 2.5%, proving higher among isolated thoracic fractures patients than among isolated lumbar fractures counterparts (11.3% vs. 4.6%, p < 0.001). Isolated thoracic fractures with SCI were significantly more likely to die than non-SCI counterparts (8.2% vs. 3.1%, p < 0.001). There were no differences in the incidence of IAIs between patients with or without SCI following thoracolumbar fracture overall or in isolated thoracic fractures; although isolated lumbar fractures patients with SCI were more likely to have renal (3.4% vs. 1.6%, p = 0.02) or bowel injuries (2.3% vs. 1.0%, p = 0.04) than the non-SCI counterparts. Conclusion: SCI in the setting of thoracolumbar fracture does not appear to be a marker for associated IAI. However, in a subset of isolated lumbar fractures, SCI patient is associated with increased risks for renal and bowel injury.
  • Hyperinsulinemic hypoglycemia, clinical considerations and a case report of a novel GCK mutation

    Kraslow, Michelle; Miller, Ann; Memon, Raafia; Pinault, Lillian; Steinle, Nanette; Spanakis, Ilias (Elsevier Inc., 2021-03-12)
    Introduction: Hypoglycemia harbors a broad differential diagnosis but is most often thought of in relation to poorly controlled diabetes. Recently however, there is growing evidence that genetic mutations, in the setting of hyperinsulinemic hypoglycemia (HH), are more common than previously noted as the primary cause of symptomatic hypoglycemia. One of 16 known genetic mutations implicated in HH is the gene that codes for the enzyme glucokinase, which has an integral role in glucose metabolism. Case: We describe the case of a 36-year-old relatively healthy male presenting with acute on chronic spells of shakiness relieved by eating who, after thorough work up for metabolic, hormonal, and structural causes of hypoglycemia, was determined to carry a previously undiscovered mutation in glucokinase that was responsible for his symptoms. Of note, his four-year-old son had already been diagnosed with HH that was successfully controlled with diazoxide by this time. Genetic testing confirmed that the patient and his son, along with the patient's father, all carried the same GCK missense variant Tyr215Phe which has not yet been documented in the scientific literature. Discussion: The patient, his father, and his son all had markedly different presentations, in both disease severity and treatment response, despite carrying the same mutation. This clinical variability within families with HH has been described before, but the specific explanation for this finding, given the apparent autosomal dominant transmission, remains poorly understood and understudied. The roles of micro RNA, the immune system, tissue specific promoters, and other individual metabolic differences in people with HH have all been explored with this in mind. We also discuss the short-term physiologic response to hypoglycemia and analyze compensatory mechanisms that those with HH may harbor to endure longer durations of hypoglycemia. Conclusion: The discovery of the new variant in the GCK gene located on chromosome 7 in this case suggests that there are still undiscovered mutations responsible for HH. This case also highlights the need for further research characterizing the physiology, phenotypic variability, and natural history of the disease, particularly as its prevalence increases in the setting of more advanced diagnostic methods. Copyright 2021 The Authors
  • Peptidomimetic inhibitor of L-plastin reduces osteoclastic bone resorption in aging female mice

    Aljohani, Hanan; Stains, Joseph P; Majumdar, Sunipa; Srinivasan, Deepa; Senbanjo, Linda; Chellaiah, Meenakshi A (Springer Nature, 2021-04-09)
    L-plastin (LPL) was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones (NSZs), which are precursor zones for mature sealing zones. TAT-fused cell-penetrating small molecular weight LPL peptide (TAT- MARGSVSDEE, denoted as an inhibitory LPL peptide) attenuated the formation of NSZs and impaired bone resorption in vitro in osteoclasts. Also, the genetic deletion of LPL in mice demonstrated decreased eroded perimeters and increased trabecular bone density. In the present study, we hypothesized that targeting LPL with the inhibitory LPL peptide in vivo could reduce osteoclast function and increase bone density in a mice model of low bone mass. We injected aging C57BL/6 female mice (36 weeks old) subcutaneously with the inhibitory and scrambled peptides of LPL for 14 weeks. Micro-CT and histomorphometry analyses demonstrated an increase in trabecular bone density of femoral and tibial bones with no change in cortical thickness in mice injected with the inhibitory LPL peptide. A reduction in the serum levels of CTX-1 peptide suggests that the increase in bone density is associated with a decrease in osteoclast function. No changes in bone formation rate and mineral apposition rate, and the serum levels of P1NP indicate that the inhibitory LPL peptide does not affect osteoblast function. Our study shows that the inhibitory LPL peptide can block osteoclast function without impairing the function of osteoblasts. LPL peptide could be developed as a prospective therapeutic agent to treat osteoporosis.
  • A novel LC-MS/MS method for determination of the potential antiviral candidate favipiravir for the emergency treatment of SARS-CoV-2 virus in human plasma: Application to a bioequivalence study in Egyptian human volunteers

    Morsy, Mosaad I; Nouman, Eman G; Abdallah, Youmna M; Zainelabdeen, Mourd A; Darwish, Mohamed M; Hassan, Ahmed Y; Gouda, Amira S; Rezk, Mamdouh R; Abdel-Megied, Ahmed M; Marzouk, Hoda M (Elsevier B.V., 2021-04-01)
    A novel, fast and sensitive LC-MS/MS method was developed and validated for the bioanalysis of the antiviral agent favipiravir (FAV); a promising candidate for treatment of SARS-CoV-2 (COVID-19) in human plasma using pyrazinamide as an internal standard (IS). Simple protein precipitation was adopted for plasma sample preparation using methanol. Chromatographic separation was accomplished on Eclipse plus C18 column (50 × 4.6 mm, 3.5 μm) using a mobile phase composed of methanol-0.2 % acetic acid (20:80, v/v) pumped at a flow rate 0.6 mL/min in an isocratic elution mode. The API4500 triple quadrupole tandem mass spectrometer was operated with multiple-reaction monitoring (MRM) in negative electrospray ionization interface for FAV and positive for IS. The MRM function was used for quantification, with the transitions set at m/z 156.00→ 113.00 and m/z 124.80→ 81.00 for FAV and IS. The method was optimized and fully validated in accordance to US-FDA guidelines. Linearity was acquired over a concentration range of 100.0-20000.0 ng/mL by computing using weighted linear regression strategy (1/x2). The proposed method was effectively applied for the pharmacokinetic evaluation of FAV and to demonstrate the bioequivalence of a new FAV formulation (test) and reference product in healthy Egyptian human volunteers.
  • Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson's disease and dementia with Lewy bodies

    Bargar, Connor; Wang, Wen; Gunzler, Steven A; LeFevre, Alexandra; Wang, Zerui; Lerner, Alan J; Singh, Neena; Tatsuoka, Curtis; Appleby, Brian; Zhu, Xiongwei; et al. (Springer Nature, 2021-04-07)
    Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSynD) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSynD aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSynD across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSynD in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSynD aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSynD in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSynD in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSynD in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSynD as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.
  • Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

    Taliun, D; Harris, D.N.; Kessler, M.D.; Mitchell, B.D.; Ament, S. (Nature Publishing Group, 2021-02-10)
    The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%. © 2021, The Author(s).
  • Freeze-dried platelets promote clot formation, attenuate endothelial cell permeability, and decrease pulmonary vascular leak in a murine model of hemorrhagic shock

    Trivedi, A.; Potter, D.R.; Miyazawa, B.Y.; Lin, M.; Vivona, L.R.; Khakoo, M.A.; Antebi, B.; Lee, A.; Ishler, B.; Dickerson, M.; et al. (Wolters Kluwer Health, 2021)
    BACKGROUND: Hemorrhagic shock (HS) and trauma induce endothelial barrier compromise, inflammation, and aberrant clotting. We have shown that fresh human platelets (Plts) and Plt extracellular vesicles mitigate vascular leak in murine models of injury. Here, we investigate the potential of freeze-dried platelets (FDPlts) to attenuate pulmonary vascular permeability, decrease inflammation, and promote clotting in a murine model of HS. METHODS: Human FDPlts were characterized using in vitro assays of Plt marker expression, aggregation, coagulation, and endothelial cell permeability. An intravital model of vascular injury in the mouse cremaster muscle was used to assess the ability of FDPlts to incorporate into clots. Mouse groups subjected to controlled hemorrhage for 90 minutes were (1) lactated Ringer solution (LR), (2) FDPlts, (3) fresh human Plts, (4) murine whole blood (WB), and (5) shams (only instrumented). Hemorrhagic shock mouse endpoints included coagulation, pulmonary vascular permeability, and lung injury. RESULTS: Freeze-dried Plts expressed Plt-specific markers and retained functionality similar to fresh Plts. In in vitro assays of Plt aggregation, differences were noted. In vivo, FDPlts and Plts were found to incorporate into clots in postcapillary venules in the mouse cremaster muscle. Hemorrhagic shock mice resuscitated with LR displayed increased pulmonary vascular permeability compared with sham (sham, 686.6 ± 359.7; shock-LR, 2,637 ± 954.7; p = 0.001), and treatment with FDPlts or WB attenuated permeability compared with shock: shock-FDPlts, 1,328 ± 462.6 (p = 0.05), and shock-WB, 1,024 ± 370.5 (p = 0.0108). However, human Plts (Days 1-3) did not attenuate vascular leak in HS mice compared with shock-LR (shock-Plts, 3,601 ± 1,581; p = 0.33). CONCLUSION: FDPlts contribute to clot formation similar to fresh human Plts. FDPlts also attenuated vascular permeability in vitro and in vivo. Mouse WB resuscitation but not fresh human Plts attenuated vascular permeability after HS. These data suggest that the effect of FDPlts may be a suitable alternative to fresh Plts in modulating hemostasis and the endotheliopathy associated with injury.
  • Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

    Patel, Y.; Carr, V.J.; HongL.E. (2021)
    Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls. Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
  • Mapping routine measles vaccination in low- and middle-income countries

    Sbarra, A.N.; Amit; A.M.L.,Memiah; P.T.N.; Local Burden of Disease Vaccine Coverage Collaborators (2021)
    The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)1�4. Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)5�8. Here we generated annual estimates of routine childhood MCV1 coverage at 5 � 5-km2 pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children.

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