Now showing items 1-20 of 6873

    • Multiplier Method for Predicting the Sitting Height Growth at Maturity: A Database Analysis.

      Jauregui, Julio J; Hlukha, Larysa P; McClure, Philip K; Paley, Dror; Shualy, Mordchai B; Goldberg, Maya B; Herzenberg, John E (2022-11-17)
      This study aims to develop multipliers for the spine and sitting height to predict sitting height at maturity. With the aid of longitudinal and cross-sectional clinical databases, we divided the total sitting height, cervical, thoracic, and lumbar lengths at skeletal maturity by these same four factors at each age for each percentile given. A series of comparisons were then carried out between the multipliers as well as the percentiles and the varied racial and ethnic groups within them. Regarding sitting height, there was little variability and correlated with the multipliers calculated for the thoracic and lumbar spine. The multiplier method has demonstrated accuracy that is not influenced by generation, percentile, race, and ethnicity. This multiplier can be used to anticipate mature sitting height, the heights of the thoracic, cervical, and lumbar spine, as well as the lack of spinal growth after spinal fusion surgery in skeletally immature individuals.
    • Immune-Mediated Pathogenesis in Dengue Virus Infection.

      Khanam, Arshi; Gutiérrez-Barbosa, Hector; Lyke, Kirsten E; Chua, Joel V (2022-11-21)
      Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. While the majority of DENV infections are mild or asymptomatic, approximately 5% of the cases develop a severe form of the disease that is mainly attributed to sequential infection with different DENV serotypes. The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. Moreover, the ability of DENV to infect a wide variety of immune cells, including monocytes, macrophages, dendritic cells, mast cells, and T and B cells, further dysregulates the antiviral functions of these cells, resulting in viral dissemination. Although several risk factors associated with disease progression have been proposed, gaps persist in the understanding of the disease pathogenesis and further investigations are warranted. In this review, we discuss known mechanisms of DENV-mediated immunopathogenesis and its association with disease progression and severity.
    • Regulation of glutamate homeostasis in the nucleus accumbens by astrocytic CB1 receptors and its role in cocaine-motivated behaviors.

      Zhang, Lan-Yuan; Kim, Andrew Y; Cheer, Joseph F (2022-05-21)
      Cannabinoid type 1 receptors (CB1Rs) orchestrate brain reward circuitry and are prevalent neurobiological targets for endocannabinoids and cannabis in the mammalian brain. Decades of histological and electrophysiological studies have established CB1R as presynaptic G-protein coupled receptors (GPCRs) that inhibit neurotransmitter release through retrograde signaling mechanisms. Recent seminal work demonstrates CB1R expression on astrocytes and the pivotal function of glial cells in endocannabinoid-mediated modulation of neuron-astrocyte signaling. Here, we review key facets of CB1R-mediated astroglia regulation of synaptic glutamate transmission in the nucleus accumbens with a specific emphasis on cocaine-directed behaviors.
    • Chlorpromazine as Treatment for Refractory Agitation Associated with Pediatric Delirium.

      Kim, Shin Young; Simone, Shari; Kishk, Omayma A; Graciano, Ana Lia; Seung, Hyunuk; Edwards, Sarah (2022-11-17)
      Objective: Delirium and agitation can be devastating and prolong the length of hospitalization. As part of our continuous improvement efforts, we implemented the use of intermittent chlorpromazine therapy to target refractory agitation associated with hyperactive or mixed delirium (RAA-D). The purpose of this study was to evaluate the effectiveness of chlorpromazine on RAA-D and delirium symptoms as well as any adverse effects in critically ill children. Methods: Retrospective chart review was conducted for children admitted to the pediatric intensive care unit who were treated with chlorpromazine for RAA-D from March 2017 to January 2019. The primary end point was to determine differences in Cornell Assessment for Pediatric Delirium (CAPD) and State Behavioral Scale (SBS) scores 24 hours before and after chlorpromazine administration. The secondary end points were the 24-hour cumulative dosing of narcotic and sedative agents before and after chlorpromazine administration and adverse events associated with chlorpromazine use. Results: Twenty-six patients were treated with chlorpromazine for RAA-D; 16 (61.5%) were male with a median age of 14.5 months (IQR, 6-48). The mean CAPD (n = 24) and median SBS (n = 23) scores were significantly lower 24 hours after chlorpromazine use when compared to baseline scores, 12 vs 8.9 (p = 0.0021) and 1 vs -1, (p = 0.0005) respectively. No significant adverse effects were observed. Conclusions: Chlorpromazine use in critically ill children with RAA-D was helpful for managing symptoms without adverse events. Further investigation is needed to evaluate the use of chlorpromazine to treat RAA-D to avoid long-term use of an antipsychotic.
    • Transradial Primary Pci Of An Anomalous Lad Originating From The Opposite Sinus Presenting As Stemi.

      Romero, Jorge Ramirez; Tschannen, William; Wermers, Jason P; Ahmad, Sarah Aftab; Khalid, Nauman (2022)
      ST-segment elevation myocardial infarction (STEMI) is a rare presentation in patients with anomalous coronary arteries. Among these patients, identification of the culprit lesion remains challenging. Furthermore, the default transradial approach advocated by the guidelines and professional societies, especially for acute coronary syndromes may pose technical challenges for the interventionalists.
    • Outcomes in ED patients with non-specific ECG findings and low high-sensitivity troponin.

      Alshaikh, Lamees M; Apple, Fred S; Christenson, Robert H; deFilippi, Christopher R; Limkakeng, Alexander T; McCord, James; Nowak, Richard M; Singer, Adam J; Peacock, W Frank (2022-11-17)
      Background: Although some emergency department risk stratification tools consider non-specific ECG findings as an aid in disposition decisions, their clinical value in patients with an initially low high-sensitivity cardiac troponin I (hsTnI) is unclear. Objective: Our purpose was to determine if non-specific ECG (ns-ECG) findings are associated with 30-day major adverse cardiac events (MACE) in ED patients presenting with suspected acute coronary syndromes (ACS) who have a low initial hsTnI. Methods: Using the prospective Siemens Atellica hsTnI Food and Drug Administration submission observational database, we conducted a retrospective cohort study of the association between ns-ECG findings (defined as left bundle branch block [LBBB], ST depression [STD], or T-wave inversions [TWI]) and 30-day MACE (death, myocardial infarction, heart failure hospitalization, or coronary revascularization). Eligible patients presented with suspected ACS to one of 29 US EDs from April 2015 to April 2016, had stable vital signs, a blood sample for hsTnI (Siemen's Atellica, Siemens Healthineers, Inc, Malvern, PA) obtained at 1, 3, and 6 hours after ED presentation, and were followed for 30 days. The relationship between 30-day outcome, initial hsTnI, and ns-ECG was evaluated using chi-square testing. Results: Of 2676 enrolled, 1313 patients met the inclusion criteria and are included in the analysis. Median (interquartile range) age was 62 years (54, 72), 54% were male, with 56% white, and 39% African American. Median (interquartile range) times from symptom onset to presentation and presentation to specimen collection were 92 (0, 216) and 146 (117, 177) minutes, respectively. The most common presenting symptoms were chest pain (84%), followed by dyspnea (9%). ECG findings were categorized as T-wave inversion or non-specific T wave changes (42%), ST depression ns-ECG ST changes (16%), or LBBB (2%). Thirty-day MACE occurred in 72 (5.5%) patients, with coronary revascularization (35 patients, 2.7%) and heart failure (25 patients, 1.9%) being the most frequent outcomes. In patients with an initial hsTnI below the limit of quantitation (LOQ) of 2.5 ng/L (n = 449), there was no association between ns-ECG changes and 30-day MACE (P = 0.42). If the hsTnI was ≥LOQ (2.5 ng/L), there were increased rates of 30-day MACE and ns-ECG findings (P = 0.01). Conclusion: In ED suspected ACS patients without unstable vital signs, and an initial hsTnI less than the LOQ (2.5 ng/L), ns-ECG findings are not associated with 30-day major adverse cardiac events. The use of ns-ECG findings in ACS disposition should be considered in the context of hsTnI levels.
    • Birth preparedness and complication readiness among husbands and its association with skilled birth attendance in southern Ethiopia.

      Yeshitila, Yordanos Gizachew; Memah, Peter (2022-11-19)
      Introduction: Birth preparedness and Complication Readiness (BPCR) promotes prompt use of skilled delivery and readiness for any complications to reduce delays in the provision of emergency care. Husband's involvement in preparation for childbirth is one way to mitigate life-threatening delays in providing care during childbirth. The current study assessed the association of the husband's involvement in birth preparedness and complication readiness with the use of skilled birth attendants. Method: A community-based cross-sectional study was conducted among 1,432 husbands. Study participants were selected from Arbaminch university health and demographic surveillance sites. Data were collected electronically using the Open Data Kit. The data were exported to STATA version 16 for analysis. Descriptive statistics were computed to describe the sociodemographic and reproductive variables of the study. The associations between birth preparedness and complication readiness practice and birth in the presence of a skilled birth attendant were assessed using multiple logistic regressions after adjusting for known confounders. Explanatory variables on bivariate logistic regression analysis were entered into multivariable logistic regression analysis, and a p-value of less than 0.05 was used to ascertain statistical significance. Results: Mean age of respondents was 33.7 (SD ± 6.2) years. Of all the respondents, 140 (10.3%) had made at least three preparations according to birth preparedness and complication readiness. After controlling for confounders through multivariable logistic regression, giving birth in the presence of a skilled birth attendant consistently increased with husbands involved in birth preparedness and complication readiness (AOR = 4.1, 95% CI: 2.5-6.9). Husbands whose wives had complications during previous pregnancy were 33% less likely to have skilled birth attendants (AOR = 0.67, 95% CI: 0.49-0.917). Moreover, husbands whose houses were near the health facilities were more likely to have skilled birth attendants for their wives (AOR = 3.93, 95% CI: 2.57-6.02). Conclusion: Husband's involvement in birth preparedness and complication readiness is strongly associated with using skilled birth attendants in Ethiopia. It is imperative that when designing husband's involvement programs targeting birth preparedness and complication readiness, programs and strategies should focus on enhancing activities that are inclusive of husbands in birth preparedness and complication education.
    • Low-level viraemia among people living with HIV in Nigeria: a retrospective longitudinal cohort study.

      Chun, Helen M; Abutu, Andrew; Milligan, Kyle; Ehoche, Akipu; Shiraishi, Ray W; Odafe, Solomon; Dalhatu, Ibrahim; Onotu, Dennis; Okoye, McPaul; Oladipo, Ademola; et al. (2022-12)
      Background: HIV transmission can occur with a viral load of at least 200 copies per mL of blood and low-level viraemia can lead to virological failure; the threshold level at which risk for virological failure is conferred is uncertain. To better understand low-level viraemia prevalence and outcomes, we analysed retrospective longitudinal data from a large cohort of people living with HIV on antiretroviral therapy (ART) in Nigeria. Methods: In this retrospective cohort study using previously collected longitudinal patient data, we estimated rates of virological suppression (≤50 copies per mL), low-level viraemia (51-999 copies per mL), virological non-suppression (≥1000 copies per mL), and virological failure (≥2 consecutive virological non-suppression results) among people living with HIV aged 18 years and older who initiated and received at least 24 weeks of ART at 1005 facilities in 18 Nigerian states. We analysed risk for low-level viraemia, virological non-suppression, and virological failure using log-binomial regression and mixed-effects logistic regression. Findings: At first viral load for 402 668 patients during 2016-21, low-level viraemia was present in 64 480 (16·0%) individuals and virological non-suppression occurred in 46 051 (11·4%) individuals. Patients with low-level viraemia had increased risk of virological failure (adjusted relative risk 2·20, 95% CI 1·98-2·43; p<0·0001). Compared with patients with virological suppression, patients with low-level viraemia, even at 51-199 copies per mL, had increased odds of low-level viraemia and virological non-suppression at next viral load; patients on optimised ART (ie, integrase strand transfer inhibitors) had lower odds than those on non-integrase strand transfer inhibitors for the same low-level viraemia range (eg, viral load ≥1000 copies per mL following viral load 400-999 copies per mL, integrase strand transfer inhibitor: odds ratio 1·96, 95% CI 1·79-2·13; p<0·0001; non-integrase strand transfer inhibitor: 3·21, 2·90-3·55; p<0·0001). Interpretation: Patients with low-level viraemia had increased risk of virological non-suppression and failure. Programmes should revise monitoring benchmarks and targets from less than 1000 copies per mL to less than 50 copies per mL to strengthen clinical outcomes and track progress to epidemic control.
    • The conversion of β-carotene to vitamin A in adipocytes drives the anti-obesogenic effects of β-carotene in mice.

      Coronel, Johana; Yu, Jianshi; Pilli, Nageswara; Kane, Maureen A; Amengual, Jaume (2022-11-15)
      Objective: The β-carotene oxygenase 1 (BCO1) is the enzyme responsible for the cleavage of β-carotene to retinal, the first intermediate in vitamin A formation. Preclinical studies suggest that BCO1 expression is required for dietary β-carotene to affect lipid metabolism. The goal of this study was to generate a gene therapy strategy that over-expresses BCO1 in the adipose tissue and utilizes the β-carotene stored in adipocytes to produce vitamin A and reduce obesity. Methods: We generated a novel adipose-tissue-specific, adeno-associated vector to over-express BCO1 (AT-AAV-BCO1) in murine adipocytes. We tested this vector using a unique model to achieve β-carotene accumulation in the adipose tissue, in which Bco1-/- mice were fed β-carotene. An AT-AAV over-expressing green fluorescent protein was utilized as control. We evaluated the adequate delivery route and optimized cellular and organ specificity, dosage, and exposure of our vectors. We also employed morphometric analyses to evaluate the effect of BCO1 expression in adiposity, as well as HPLC and mass spectrometry to quantify β-carotene and retinoids in tissues, including retinoic acid. Results: AT-AAV-BCO1 infusions in the adipose tissue of the mice resulted in the production of retinoic acid, a vitamin A metabolite with strong effects on gene regulation. AT-AAV-BCO1 treatment also reduced adipose tissue size and adipocyte area by 35% and 30%, respectively. These effects were sex-specific, highlighting the complexity of vitamin A metabolism in mammals. Conclusions: The over-expression of BCO1 through delivery of an AT-AAV-BCO1 leads to the conversion of β-carotene to vitamin A in adipocytes, which subsequently results in reduction of adiposity. These studies highlight for the first time the potential of adipose tissue β-carotene as a target for BCO1 over-expression in the reduction of obesity.
    • Efficacy and Safety of Temporary in situ Stenting of Ahmed Glaucoma Valve in Eyes with High Risk of Hypotony.

      Al Houssien, Abdullah Omar; Al Owaifeer, Adi Mohammed; Ahmad, Sameer I; Owaidhah, Ohoud; Malik, Rizwan (2022-11-09)
      Introduction and objective: To describe a novel technique for providing external ligation of the Ahmed glaucoma valve (AGV) to prevent hypotony in eyes at high risk with a 4/0 nylon stent suture and report outcomes compared to ligation with an absorbable vicryl suture and no ligation in terms of efficacy and safety. Methods: This was a retrospective cohort study investigating the efficacy and safety of in situ stenting compared to an absorbable ligature and the standard care, in high risk eyes, of hypotony. It included 116 patients; 34 in Group A (ligation + stent), 27 in Group B (ligation - stent), and 55 in Group C (no ligation). Results: The mean age (in years) of the participants was 53.94±19.01 in Group A, 44.85±29.92 in Group B and 52.62±24.47 in Group C, 59% (n = 20), 63% (n = 17) and 60% (n = 33) were males, respectively. The follow-up period was at least 6 months (Group A: 9.1±4.2 months, Group B: 9.6±3.4 months and Group C: 10.2±6.4 months). The mean baseline Snellen VA (LogMAR) was 1.82±1.34, 1.30±0.98 and 1.34±1.07 and the mean baseline IOP was 32.50±9.48, 28.22±7.12 and 28.33±10.63 mmHg, in Groups A, B and C, respectively. The failure rates, by the Kaplan Meier Survival curve, were higher 27.3% in Group C (no ligation) compared to 20.6% in Group A (ligation + stent) and 18.5% in Group B (ligation - stent) yet not found to be statistically significant (p = 0.4; log rank test). There was lower hypotony 2.9% in Group A and lower complications 25.9% in Group B but no statistical significance was found amongst the groups. Conclusion: In conclusion, temporary nylon in situ stenting of AGV had lower rates of hypotony. Furthermore, lower failure and complication rates were observed in vicryl only ligated AGV, then nylon in situ stented AGV and lastly in standard AGV controls.
    • MSC-EV therapy for bone/cartilage diseases.

      Kodama, Joe; Wilkinson, Kevin J; Otsuru, Satoru (2022-11-09)
      Mesenchymal stromal cells (MSCs) have been utilized in cell therapy for various diseases. Recent studies have demonstrated that extracellular vesicles (EVs) released by MSCs play an important role in their therapeutic activities. EVs contain a variety of bioactive molecules such as proteins, messenger RNAs (mRNAs), and micro RNAs (miRNAs) and modify the function of the recipient cells by transferring these molecules. Despite the promising potential of EV therapy as a substitute for MSC therapy, there are challenges that need to be addressed for the clinical success of EV therapy. EV quality has been shown to vary from batch to batch and preparation to preparation. As the consistency and reproducibility of therapeutic effects rely on the quality of EVs, it is necessary to establish techniques to manufacture scalable amounts of EVs with the same quality. In this manuscript, we discuss the potential factors that affect EV quality. We then introduce pre-clinical studies of EV therapy for bone/cartilage diseases such as osteoarthritis, rheumatoid arthritis, and osteoporosis.
    • Binding and Functional Folding (BFF): A Physiological Framework for Studying Biomolecular Interactions and Allostery.

      Young, Brianna D; Cook, Mary E; Costabile, Brianna K; Samanta, Riya; Zhuang, Xinhao; Sevdalis, Spiridon E; Varney, Kristen M; Mancia, Filippo; Matysiak, Silvina; Lattman, Eaton; et al. (2022-10-28)
      EF-hand Ca2+-binding proteins (CBPs), such as S100 proteins (S100s) and calmodulin (CaM), are signaling proteins that undergo conformational changes upon increasing intracellular Ca2+. Upon binding Ca2+, S100 proteins and CaM interact with protein targets and induce important biological responses. The Ca2+-binding affinity of CaM and most S100s in the absence of target is weak (CaKD > 1 μM). However, upon effector protein binding, the Ca2+ affinity of these proteins increases via heterotropic allostery (CaKD < 1 μM). Because of the high number and micromolar concentrations of EF-hand CBPs in a cell, at any given time, allostery is required physiologically, allowing for (i) proper Ca2+ homeostasis and (ii) strict maintenance of Ca2+-signaling within a narrow dynamic range of free Ca2+ ion concentrations, [Ca2+]free. In this review, mechanisms of allostery are coalesced into an empirical "binding and functional folding (BFF)" physiological framework. At the molecular level, folding (F), binding and folding (BF), and BFF events include all atoms in the biomolecular complex under study. The BFF framework is introduced with two straightforward BFF types for proteins (type 1, concerted; type 2, stepwise) and considers how homologous and nonhomologous amino acid residues of CBPs and their effector protein(s) evolved to provide allosteric tightening of Ca2+ and simultaneously determine how specific and relatively promiscuous CBP-target complexes form as both are needed for proper cellular function.
    • Violation of the Subtalar Joint With Novel Suture Tape Augmentation of Lateral Ligament Reconstruction: A Report of 2 Cases.

      Kung, Justin E; Hallman, Mitchell J; Humbyrd, Casey Jo (2022-11-13)
      The modified Broström-Gould operation is the gold standard for surgical treatment of chronic lateral ankle instability.2,4 Modified Broström-Gould repair with the InternalBrace (IB) is a relatively new technique promoted as providing additional biomechanical advantage resulting in early mobility during recovery and quicker return to activity.6 Although the IB has a reportedly low complication profile, with the rise in its usage, providers should be aware of potential detrimental complications.8 Intra-articular placement of suture anchors is a potential complication warned against in the manufacturer surgical technique videos of the IB; however, to our knowledge, this complication has yet to be reported in the literature.1,3 In the current article, we present 2 cases of suture anchor violation of the subtalar joint during IB augmentation for lateral ligamentous complex repair of the ankle. Both patients were informed that the data concerning their cases would be submitted for publication, and both provided verbal consent.
    • Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus.

      Durie, Ian A; Tehrani, Zahra R; Karaaslan, Elif; Sorvillo, Teresa E; McGuire, Jack; Golden, Joseph W; Welch, Stephen R; Kainulainen, Markus H; Harmon, Jessica R; Mousa, Jarrod J; et al. (2022-11-26)
      Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective against a wide swath of CCHFV strains.
    • Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats.

      Adeyemo, Tayo; Jaiyesimi, Ayodele; Bumgardner, Jill G; Lohr, Charity; Banerjee, Aditi; McKenna, Mary C; Waddell, Jaylyn (2022-11-12)
      Choline is an essential nutrient with many roles in brain development and function. Supplementation of choline in early development can have long-lasting benefits. Our experiments aimed to determine the efficacy of choline supplementation in a postnatal day (PND) 10 rat model of neonatal hypoxia ischemia (HI) at term using both male and female rat pups. Choline (100 mg/kg) or saline administration was initiated the day after birth and given daily for 10 or 14 consecutive days. We determined choline's effects on neurite outgrowth of sex-specific cultured cerebellar granule cells after HI with and without choline. The magnitude of tissue loss in the cerebrum was determined at 72 h after HI and in adult rats. The efficacy of choline supplementation in improving motor ability and learning, tested using eyeblink conditioning, were assessed in young adult male and female rats. Overall, we find that choline improves neurite outgrowth, short-term histological measures and learning ability in males. Surprisingly, choline did not benefit females, and appears to exacerbate HI-induced changes.
    • SARS-CoV-2 infection induces activation of ferroptosis in human placenta.

      Wang, Bingbing; Shen, Wei-Bin; Yang, Peixin; Turan, Sifa (2022-11-08)
      Ferroptosis, a regulated non-apoptotic form of cell death, has been implicated in the response to varied types of infectious agents including virus. In this study, we sought to determine whether SARS-CoV-2 infection can induce activation of ferroptosis in the human placenta. We collected placentas from 23 pregnant females with laboratory-confirmed SARS-CoV-2 following delivery and then used RNA in situ hybridization assay for detection of viral positive-sense strand (PSS) to confirm that these placentas have been infected. We also used immunohistochemistry assay to assess expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), an essential executioner of ferroptosis in the same specimens. Our results showed that ACSL4 expression was significantly increased in the group with positive positive-sense strand staining compared to their negative counterparts (p = 0.00022). Furthermore, we found that there was a positive trend for increased PSS staining along with increased ACSL4 expression. Our study supports that ferroptosis is activated in the response to SARS-CoV-2 infection in the human placenta, highlighting a molecular mechanism potentially linking this coronavirus infection and pathogenesis of adverse pregnancy outcomes.
    • Editorial: The role of glycans in infectious disease, Volume II.

      Martínez-Duncker, Iván; Mora-Montes, Héctor M; Vasta, Gerardo R; Chiodo, Fabrizio (2022-11-04)
      Volume 2 of “The role of glycans in infectious disease” Research Topic offers a continuity of research articles highlighting the evolving relevance of the glycocode at the interphase of pathogens and human disease, where it modulates the dynamics of bacterial, viral and fungal infections through finely tuned mechanisms. In this sense, mucosal surfaces are probably the sites where the most complex host-microbe interactions take place. In an original research article, Suwandi et al. characterize the role of the beta-1,4-N-acetylgalactosaminyltransferase enzyme (B4galnt2) in modulating infections by Citrobacter rodentium, a murine model pathogen for human enteropathogenic and enterohemorrhagic Escherichia coli. Escherichia coli is a gram-negative bacteria that can usually colonizes the human gut, but can cause intestinal or extraintestinal infections, including severe invasive disease such as bacteremia and sepsis. In this regard, E. coli is the most common cause of bacteremia in high-income countries and is a leading cause of meningitis in neonates (Bonten et al., 2021). Through the use of adhesion assays based on intestinal epithelial organoid-derived monolayers from B4galnt2−/− and B4galnt2+/+ mice the authors show that lack of this enzyme causes increased C. rodentium adherence, promoting increased inflammation and less proficiency in pathogen clearance by the host. The enhanced pathogen adhesion is dependent on the interaction of type 1 fimbriae and host mannosylated glycans that are increased as a result of deficient B4galnt2, as revealed by increased staining of the Galanthus nivalis lectin. These novel findings contribute to establish a more precise role of this enzyme in modulating host-pathogen interactions, but also in the establishment of gut microbiota.
    • Breakthrough SARS-CoV-2 Infections after Vaccination in North Carolina.

      Uschner, Diane; Bott, Matthew; Lagarde, William H; Keating, Joseph; Tapp, Hazel; Berry, Andrea A; Seals, Austin L; Munawar, Iqra; Schieffelin, John; Yukich, Joshua; et al. (2022-11-13)
      We characterize the overall incidence and risk factors for breakthrough infection among fully vaccinated participants in the North Carolina COVID-19 Community Research Partnership cohort. Among 15,808 eligible participants, 638 reported a positive SARS-CoV-2 test after vaccination. Factors associated with a lower risk of breakthrough in the time-to-event analysis included older age, prior SARS-CovV-2 infection, higher rates of face mask use, and receipt of a booster vaccination. Higher rates of breakthrough were reported by participants vaccinated with BNT162b2 or Ad26.COV2.S compared to mRNA-1273, in suburban or rural counties compared to urban counties, and during circulation of the Delta and Omicron variants.
    • Span of regularization for solution of inverse problems with application to magnetic resonance relaxometry of the brain.

      Bi, Chuan; Ou, M Yvonne; Bouhrara, Mustapha; Spencer, Richard G (2022-11-23)
      We present a new regularization method for the solution of the Fredholm integral equation (FIE) of the first kind, in which we incorporate solutions corresponding to a range of Tikhonov regularizers into the end result. This method identifies solutions within a much larger function space, spanned by this set of regularized solutions, than is available to conventional regularization methods. An additional key development is the use of dictionary functions derived from noise-corrupted inversion of the discretized FIE. In effect, we combine the stability of solutions with greater degrees of regularization with the resolution of those that are less regularized. The span of regularizations (SpanReg) method may be widely applicable throughout the field of inverse problems.
    • Persistence and Evolution of Vaginal Bacterial Strains over a Multiyear Time Period.

      France, Michael; Ma, Bing; Ravel, Jacques (2022-11-22)
      It is not clear whether the bacterial strains that comprise our microbiota are mostly long-term colonizers or transient residents. Studies have demonstrated decades-long persistence of bacterial strains within the gut, but persistence at other body sites has yet to be determined. The vaginal microbiota (VMB) is often dominated by Lactobacillus, although it is also commonly comprised of a more diverse set of other facultative and obligate anaerobes. Longitudinal studies have demonstrated that these communities can be stable over several menstrual cycles or can fluctuate temporally in species composition. We sought to determine whether the bacterial strains that comprise the VMB were capable of persisting over longer time periods. We performed shotgun metagenomics on paired samples from 10 participants collected 1 and 2 years apart. The resulting sequences were de novo assembled and binned into high-quality metagenome assembled genomes. Persistent strains were identified based on the sequence similarity between the genomes present at the two time points and were found in the VMB of six of the participants, three of which had multiple persistent strains. The VMB of the remaining four participants was similar in species composition at the two time points but was comprised of different strains. For the persistent strains, we were able to identify the mutations that were fixed in the populations over the observed time period, giving insight into the evolution of these bacteria. These results indicate that bacterial strains can persist in the vagina for extended periods of time, providing an opportunity for them to evolve in the host microenvironment. IMPORTANCE: The stability of strains within the vaginal microbiota is largely uncharacterized. Should these strains be capable of persisting for extended periods of time, they could evolve within their host in response to selective pressures exerted by the host or by other members of the community. Here, we present preliminary findings demonstrating that bacterial strains can persist in the vagina for at least 1 year. We further characterized in vivo evolution of the persistent strains. Several participants were also found to not have persistent strains, despite having a vaginal microbiota (VMB) with similar species composition at the two time points. Our observations motivate future studies that collect samples from more participants, at more time points, and over even longer periods of time. Understanding which strains persist, what factors drive their persistence, and what selective pressures they face will inform the development and delivery of rationally designed live biotherapeutics for the vagina.