Publications by authors named "Robert Edwards"

1,109 Publications

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RaFAH: Host prediction for viruses of Bacteria and Archaea based on protein content.

Patterns (N Y) 2021 Jul 15;2(7):100274. Epub 2021 Jun 15.

Evolutionary Genomics Group, Departamento de Producción Vegetal y Microbiología, Universidad Miguel Hernández, Aptdo. 18., Ctra. Alicante-Valencia N-332, s/n, San Juan de Alicante, 03550 Alicante, Spain.

Culture-independent approaches have recently shed light on the genomic diversity of viruses of prokaryotes. One fundamental question when trying to understand their ecological roles is: which host do they infect? To tackle this issue we developed a machine-learning approach named Random Forest Assignment of Hosts (RaFAH), that uses scores to 43,644 protein clusters to assign hosts to complete or fragmented genomes of viruses of Archaea and Bacteria. RaFAH displayed performance comparable with that of other methods for virus-host prediction in three different benchmarks encompassing viruses from RefSeq, single amplified genomes, and metagenomes. RaFAH was applied to assembled metagenomic datasets of uncultured viruses from eight different biomes of medical, biotechnological, and environmental relevance. Our analyses led to the identification of 537 sequences of archaeal viruses representing unknown lineages, whose genomes encode novel auxiliary metabolic genes, shedding light on how these viruses interfere with the host molecular machinery. RaFAH is available at https://sourceforge.net/projects/rafah/.
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http://dx.doi.org/10.1016/j.patter.2021.100274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276007PMC
July 2021

A Provider Perspective of Psychosocial Predictors of Upper-Extremity Vascularized Composite Allotransplantation Success.

J Hand Surg Am 2021 Jul 12. Epub 2021 Jul 12.

Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA. Electronic address:

Purpose: We performed a qualitative study to understand the psychosocial factors associated with success in upper-extremity vascularized composite allotransplantation from the perspective of transplant providers.

Methods: We recruited 13 providers actively involved in upper-extremity vascularized composite allotransplantation. Participants included physicians, nurses, social workers, occupational therapists, and research administrators. We conducted semistructured face-to-face focus group interviews using a guide that explored providers' perceptions of qualities contributing to transplant outcome. Topics included social support networks and their influence on recovery, barriers to treatment compliance and successful posttransplant rehabilitation, and the process of setting patients' expectations. We performed a thematic analysis that produced a list of themes, subthemes, and proposed hypotheses explaining how the themes related to the study's guiding questions.

Results: The analysis identified numerous factors that contribute to transplant success: (1) recipients' prior experiences modify their ability to cope and adapt after transplantation, (2) behaviors and characteristics such as positivity influence candidacy and may be predictive of successful outcomes, and (3) social support is essential for improved function and compliance. The provider care team cited difficulty in predicting recipient compliance and in setting realistic expectations.

Conclusions: Motivated recipients with developed coping and resiliency, a positive attitude, and stable, physically-able caregivers are perceived by providers to have greater success after transplantation.

Clinical Relevance: Findings from this work may help providers determine optimal candidates for upper-extremity vascularized composite allotransplantation.
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http://dx.doi.org/10.1016/j.jhsa.2021.05.005DOI Listing
July 2021

In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies.

Cell 2021 Jun 18. Epub 2021 Jun 18.

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.
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http://dx.doi.org/10.1016/j.cell.2021.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232969PMC
June 2021

Methadone maintenance patients lack analgesic response to a cumulative intravenous dose of 32 mg of hydromorphone.

Drug Alcohol Depend 2021 Jun 25;226:108869. Epub 2021 Jun 25.

University of California, San Francisco, Department of Psychiatry and Behavioral Sciences, 401 Parnassus Ave, San Francisco, CA, 94143, USA; Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Ward 95, San Francisco, CA, 94110, USA. Electronic address:

Objectives: Acute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST).

Methods: Individuals (N = 8) without chronic pain were maintained on 80-100 mg/day of oral methadone. Participants received four IV, escalating/incremental doses of hydromorphone over 270 min (32 mg total) or four placebo doses within a session test day. Test sessions were scheduled at least one week apart. QST and abuse liability measures were administered at baseline and after each injection.

Results: No significant differences between the hydromorphone and placebo control conditions on analgesic indices for any QST outcomes were detected. Similarly, no differences on safety or abuse liability indices were detected despite the high doses of hydromorphone utilized. Few adverse events were detected, and those reported were mild in severity.

Conclusions: The findings demonstrate that methadone-maintained individuals are highly insensitive to the analgesic effects of high-dose IV hydromorphone and may require very high doses of opioids, more efficacious opioids, or combined non-opioid analgesic strategies to achieve adequate analgesia.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108869DOI Listing
June 2021

No Evidence Known Viruses Play a Role in the Pathogenesis of Onchocerciasis-Associated Epilepsy. An Explorative Metagenomic Case-Control Study.

Pathogens 2021 Jun 22;10(7). Epub 2021 Jun 22.

Viral Information Institute, Biology Department, San Diego State University, San Diego, CA 92182, USA.

Despite the increasing epidemiological evidence that the parasite is strongly associated with epilepsy in children, hence the name onchocerciasis-associated epilepsy (OAE), the pathophysiological mechanism of OAE remains to be elucidated. In June 2014, children with unprovoked convulsive epilepsy and healthy controls were enrolled in a case control study in Titule, Bas-Uélé Province in the Democratic Republic of the Congo (DRC) to identify risk factors for epilepsy. Using a subset of samples collected from individuals enrolled in this study (16 persons with OAE and 9 controls) plasma, buffy coat, and cerebrospinal fluid (CSF) were subjected to random-primed next-generation sequencing. The resulting sequences were analyzed using sensitive computational methods to identify viral DNA and RNA sequences. (), , (Human polyomavirus), and were identified in cases and in controls. Not unexpectedly, a variety of bacteriophages were also detected in all cases and controls. However, none of the identified viral sequences were found enriched in OAE cases, which was our criteria for agents that might play a role in the etiology or pathogenesis of OAE.
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http://dx.doi.org/10.3390/pathogens10070787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308762PMC
June 2021

Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity.

Science 2021 Jun 24. Epub 2021 Jun 24.

Duke Human Vaccine Institute, Durham, NC 27710, USA.

SARS-CoV-2 variants with multiple spike mutations enable increased transmission and antibody resistance. Here, we combine cryo-EM, binding and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased ACE2 receptor binding and increased propensity for RBD up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either inter-species transmission or escape from antibody neutralization.
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http://dx.doi.org/10.1126/science.abi6226DOI Listing
June 2021

Growth faltering regardless of chronic diarrhea is associated with mucosal immune dysfunction and microbial dysbiosis in the gut lumen.

Mucosal Immunol 2021 Jun 22. Epub 2021 Jun 22.

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.

Despite the impact of childhood diarrhea on morbidity and mortality, our understanding of its sequelae has been significantly hampered by the lack of studies that examine samples across the entire intestinal tract. Infant rhesus macaques are naturally susceptible to human enteric pathogens and recapitulate the hallmarks of diarrheal disease such as intestinal inflammation and growth faltering. Here, we examined intestinal biopsies, lamina propria leukocytes, luminal contents, and fecal samples from healthy infants and those experiencing growth faltering with distant acute or chronic active diarrhea. We show that growth faltering in the presence or absence of active diarrhea is associated with a heightened systemic and mucosal pro-inflammatory state centered in the colon. Moreover, polyclonal stimulation of colonic lamina propria leukocytes resulted in a dampened cytokine response, indicative of immune exhaustion. We also detected a functional and taxonomic shift in the luminal microbiome across multiple gut sites including the migration of Streptococcus and Prevotella species between the small and large intestine, suggesting a decompartmentalization of gut microbial communities. Our studies provide valuable insight into the outcomes of diarrheal diseases and growth faltering not attainable in humans and lays the groundwork to test interventions in a controlled and reproducible setting.
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http://dx.doi.org/10.1038/s41385-021-00418-2DOI Listing
June 2021

Individual variation in diurnal cortisol in patients with knee osteoarthritis: Clinical correlates.

Int J Psychophysiol 2021 Jun 15;167:1-6. Epub 2021 Jun 15.

Department of Anesthesiology, Harvard Medical School, Brigham & Women's Hospital, 850 Boylston St, Suite 302, Chestnut Hill, MA 02467, USA.

Background: The cortisol awakening response (CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation. To date, however, studies of HPA-axis function among patients with chronic pain are scarce and show equivocal results. The objectives of this study were to investigate the association between CAR and pain-related outcomes and to investigate potential sex differences in patients with knee osteoarthritis (KOA).

Methods: In this cross-sectional study, KOA patients (N = 96) completed self-report questionnaires assessing pain and psychosocial factors and underwent Quantitative Sensory Testing (QST) to assess pressure pain threshold (PPT). Additionally, salivary cortisol samples (N = 60) were collected to assess HPA-axis function at 6 time points (awakening, 15- and 30-minute post-awakening, 4 PM, 9 PM and bedtime). The CAR was calculated by examining increases in salivary cortisol from awakening to 30 min post awakening and the total post-awakening cortisol concentration by calculating the lower areas under the curve of cortisol with respect to ground (AUC).

Results: Patients with a relatively blunted CAR had significantly higher anxiety levels and lower PPT than patients with relatively normal CAR. Similarly, patients with a relatively reduced AUC had significantly higher pain interference and anxiety levels compared to patients with relatively normal AUC. PPT was positively correlated with CAR and AUC and negatively correlated with pain severity and anxiety Men with KOA had significantly lower anxiety, higher PPT and higher CAR and AUC than women with KOA. Mediation analysis results revealed a significant indirect effect of PPT on the relationship between sex and AUC CONCLUSIONS: The findings of this study suggest that neuroendocrine factors such as CAR and AUC may contribute to individual differences in pain-related outcomes in patients with KOA. Additionally, our results show sex differences in the magnitude of morning HPA activation and pain-related outcomes. Finally, our findings are suggestive of a sex-dependent relationship between post-awakening cortisol concentrations and pain perception. Future research should examine these associations across various pain populations.
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http://dx.doi.org/10.1016/j.ijpsycho.2021.06.004DOI Listing
June 2021

3D magnetic resonance spectroscopic imaging reveals links between brain metabolites and multidimensional pain features in fibromyalgia.

Eur J Pain 2021 Jun 8. Epub 2021 Jun 8.

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

Background: Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood.

Methods: We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87).

Results: Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus.

Conclusions: These findings support single voxel placement targeting nociceptive processing areas in prior H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia.

Significance: This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.
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http://dx.doi.org/10.1002/ejp.1820DOI Listing
June 2021

Functional Homology for Antibody-Dependent Phagocytosis Across Humans and Rhesus Macaques.

Front Immunol 2021 20;12:678511. Epub 2021 May 20.

Department of Surgery, Duke University School of Medicine, Durham, NC, United States.

Analyses of human clinical HIV-1 vaccine trials and preclinical vaccine studies performed in rhesus macaque (RM) models have identified associations between non-neutralizing Fc Receptor (FcR)-dependent antibody effector functions and reduced risk of infection. Specifically, antibody-dependent phagocytosis (ADP) has emerged as a common correlate of reduced infection risk in multiple RM studies and the human HVTN505 trial. This recurrent finding suggests that antibody responses with the capability to mediate ADP are most likely a desirable component of vaccine responses aimed at protecting against HIV-1 acquisition. As use of RM models is essential for development of the next generation of candidate HIV-1 vaccines, there is a need to determine how effectively ADP activity observed in RMs translates to activity in humans. In this study we compared ADP activity of human and RM monocytes and polymorphonuclear leukocytes (PMN) to bridge this gap in knowledge. We observed considerable variability in the magnitude of monocyte and PMN ADP activity across individual humans and RM that was not dependent on FcR alleles, and only modestly impacted by cell-surface levels of FcRs. Importantly, we found that for both human and RM phagocytes, ADP activity of antibodies targeting the CD4 binding site was greatest when mediated by human IgG3, followed by RM and human IgG1. These results demonstrate that there is functional homology between antibody and FcRs from these two species for ADP. We also used novel RM IgG1 monoclonal antibodies engineered with elongated hinge regions to show that hinge elongation augments RM ADP activity. The RM IgGs with engineered hinge regions can achieve ADP activity comparable to that observed with human IgG3. These novel modified antibodies will have utility in passive immunization studies aimed at defining the role of IgG3 and ADP in protection from virus challenge or control of disease in RM models. Our results contribute to a better translation of human and macaque antibody and FcR biology, and may help to improve testing accuracy and evaluations of future active and passive prevention strategies.
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http://dx.doi.org/10.3389/fimmu.2021.678511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174565PMC
May 2021

Chronic pain severity, impact, and opioid use among patients with cancer: An analysis of biopsychosocial factors using the CHOIR learning health care system.

Cancer 2021 Jun 1. Epub 2021 Jun 1.

Division of Pain Medicine, Department of Anesthesiology, Perioperative Medicine, and Pain Medicine, Stanford University, Stanford, California.

Background: Despite the biopsychosocial underpinnings of chronic noncancer pain, relatively little is known about the contribution of psychosocial factors to chronic cancer pain. The authors aimed to characterize associations between biopsychosocial factors and pain and opioid use among individuals with chronic pain and cancer.

Methods: The authors conducted a retrospective, cross-sectional study of 700 patients with chronic pain and cancer seeking treatment at an academic tertiary pain clinic. Patients completed demographic questionnaires and validated psychosocial and pain measures. Multivariable, hierarchical linear and logistic regressions assessed the relative contributions of biopsychosocial factors to the primary dependent variables of pain severity, pain interference, and opioid use.

Results: Participants were 62% female and 66% White with a mean age of 59 ± 15 years, and 55% held a college degree or higher. Older age, African American or "other" race, sleep disturbance, and pain catastrophizing were significantly associated with higher pain severity (F(5,657) = 22.45; P ≤ .001; R = 0.22). Depression, sleep disturbance, pain catastrophizing, lower emotional support, and higher pain severity were significantly associated with pain interference (F(5,653) = 9.47; P ≤ .001; R = 0.44). Lastly, a poor cancer prognosis (Exp(B) = 1.62) and sleep disturbance (Exp(B) = 1.02) were associated with taking opioids, whereas identifying as Asian (Exp(B) = 0.48) or Hispanic (Exp(B) = 0.47) was associated with lower odds of using opioids.

Conclusions: Modifiable psychological factors-specifically sleep disturbance, depression, and pain catastrophizing-were uniquely associated with pain and opioid use in patients with chronic pain and diverse cancer diagnoses. Future behavioral pain interventions that concurrently target sleep may improve pain among patients with cancer.

Lay Summary: Feeling depressed, worrying about pain, and bad sleep are related to higher pain symptoms in individuals with chronic pain and cancer. Specifically, those who struggle to sleep have worse pain and use more opioids. Also, individuals who have a bad prognosis for their cancer are more likely to be using opioid pain medications. Although race and cancer are related to chronic pain in patients, psychological well-being is also strongly related to this same pain.
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http://dx.doi.org/10.1002/cncr.33645DOI Listing
June 2021

Higher Pain Sensitivity Predicts Efficacy of a Wearable Transcutaneous Electrical Nerve Stimulation Device for Persons With Fibromyalgia: A Randomized Double-Blind Sham-Controlled Trial.

Neuromodulation 2021 May 30. Epub 2021 May 30.

Pain Management Center, Brigham and Women's Hospital, Harvard Medical School, Chestnut Hill, MA, USA.

Objectives: This study investigated the efficacy of a transcutaneous electrical nerve stimulation (TENS) device (Quell®) for persons with symptoms due to fibromyalgia (FM).

Materials And Methods: One hundred nineteen (N = 119) subjects were randomly assigned to use an active (N = 62) or sham (N = 57) TENS for three months. All subjects completed baseline questionnaires and were administered quantitative sensory testing (QST). Subjects completed the Patients' Global Impression of Change (PGIC, primary outcome measure) and other mailed questionnaires (secondary outcome measures) at six weeks and three months.

Results: The subjects averaged 50.4 ± 13.5 years of age, 93.3% were female, and 79.8% were Caucasian. Most showed benefit from using the TENS, but no differences between groups were found on the primary outcome measure after three months (active 3.87 ± 1.85, sham 3.73 ± 1.80, 95% confidence interval [CI] [-0.60, 0.88], p = 0.707). Those with more hypersensitivity showed most improvement on the PGIC at six weeks (0.22, 95% CI [0.01, 0.43], p = 0.042) and three months (0.20, 95% CI [0.00, 0.41], p = 0.049) and among those with higher sensitivity based on QST, the active TENS group showed the most benefit with TENS compared with the sham treatment (1.20, 95% CI [0.22, 2.18], p = 0.017). No TENS-related serious adverse events were reported. Subjects in the sham group correctly identified their treatment 87.5% of the time, while, surprisingly, subjects in the active group correctly identified their treatment only 17.4% of the time.

Conclusion: This study found no differences between those who were exposed to maximal-frequency active stimulation or minimal-frequency sham stimulation from a wearable TENS in reducing FM-related symptoms. However, those with greater hypersensitivity showed most benefit from TENS. Additional studies to help determine the role individual differences play in the use of TENS in managing FM-related symptoms are needed.
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http://dx.doi.org/10.1111/ner.13463DOI Listing
May 2021

Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.

Nature 2021 06 10;594(7864):553-559. Epub 2021 May 10.

Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA.

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2). Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.
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http://dx.doi.org/10.1038/s41586-021-03594-0DOI Listing
June 2021

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice.

bioRxiv 2021 Apr 28. Epub 2021 Apr 28.

SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.
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http://dx.doi.org/10.1101/2021.04.27.441655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095197PMC
April 2021

Gut Microbiota Represent a Major Thermogenic Biomass.

Function (Oxf) 2021 15;2(3):zqab019. Epub 2021 Apr 15.

Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.

Evidence supports various roles for microbial metabolites in the control of multiple aspects of host energy flux including feeding behaviors, digestive efficiency, and energy expenditure, but few studies have quantified the energy utilization of the biomass of the gut microbiota itself. Because gut microbiota exist in an anoxic environment, energy flux is expected to be anaerobic; unfortunately, commonly utilized O/CO respirometry-based approaches are unable to detect anaerobic energy flux. To quantify the contribution of the gut microbial biomass to whole-animal energy flux, we examined the effect of surgical reduction of gut biomass in C57BL/6J mice via cecectomy and assessed energy expenditure using methods sensitive to anaerobic flux, including bomb and direct calorimetry. First, we determined that cecectomy caused an acceleration of weight gain over several months due to a reduction in combined total host plus microbial energy expenditure, as reflected by an increase in energy efficiency (ie, weight gained per calorie absorbed). Second, we determined that under general anesthesia, cecectomy caused immediate changes in heat dissipation that were significantly modified by short-term pretreatment with dietary or pharmaceutical interventions known to modify the microbiome, and confirmed that these effects were undetectable by respirometry. We conclude that while the cecum only contributes approximately 1% of body mass in the mouse, this organ contributes roughly 8% of total resting energy expenditure, that this contribution is predominantly anaerobic, and that the composition and abundance of the cecal microbial contents can significantly alter its contribution to energy flux.
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http://dx.doi.org/10.1093/function/zqab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055641PMC
April 2021

Genome-Wide B Cell, CD4, and CD8 T Cell Epitopes That Are Highly Conserved between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Targets for Preemptive Pan-Coronavirus Vaccines.

J Immunol 2021 06 28;206(11):2566-2582. Epub 2021 Apr 28.

Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA;

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4 and CD8 T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4 and CD8 T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4 and CD8 T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.
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http://dx.doi.org/10.4049/jimmunol.2001438DOI Listing
June 2021

Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score.

mSphere 2021 04 28;6(2). Epub 2021 Apr 28.

Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, USA

Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, enzyme-linked immunosorbent assay (ELISA) and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients ( = 86) experiencing a wide range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the intensive care unit (ICU), requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within 6 days post-symptom onset and sometimes within 1 day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient's comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 likelihood ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention. The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.
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http://dx.doi.org/10.1128/mSphere.00203-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092137PMC
April 2021

Cancer pain self-management in the context of a national opioid epidemic: Experiences of patients with advanced cancer using opioids.

Cancer 2021 Apr 27. Epub 2021 Apr 27.

Harvard Medical School, Boston, Massachusetts.

Background: The US opioid epidemic has prompted dramatic changes in public attitudes and regulations governing opioid prescribing. Little is known about the experiences of patients with advanced cancer using opioids in the context of the epidemic.

Methods: Semistructured interviews of 26 patients with advanced cancer were conducted between May 2019 and April 2020; their experiences self-managing chronic pain with opioids were evaluated.

Results: Patients consistently described the negative impact of the opioid epidemic on their ability to self-manage pain. Negative media coverage and personal experiences with the epidemic promoted stigma, fear, and guilt surrounding opioid use. As a result, many patients delayed initiating opioids and often viewed their decision to take opioids as a moral failure-as "caving in." Patients frequently managed this internal conflict through opioid-restricting behaviors (eg, skipping or taking lower doses). Stigma also impeded patient-clinician communication; patients often avoided discussing opioids or purposely conveyed underusing them to avoid being labeled a "pill seeker." Patients experienced structural barriers to obtaining opioids such as prior authorizations, delays in refills, or being questioned by pharmacists about their opioid use. Barriers were stressful, amplified stigma, interfered with pain control, and reinforced ambivalence about opioids.

Conclusions: The US opioid epidemic has stigmatized opioid use and undermined pain management in individuals with advanced cancer. Interventions seeking to alleviate cancer pain should attend to the multiple, negative influences of the opioid crisis on patients' ability to self-manage.

Lay Summary: Patients with advanced cancer suffer from significant pain and frequently receive opioids to manage their pain. Of the 26 patients with advanced cancer interviewed, the majority of patients experienced stigma about their opioid use for cancer pain management. All patients felt that the opioid epidemic fostered this stigma. Several struggled to use opioids for pain because of this stigma and the logistical complications they experienced with pharmacies and insurance coverage. Many were afraid to share their concerns about opioids with their providers. ​.
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http://dx.doi.org/10.1002/cncr.33532DOI Listing
April 2021

Syphilis among men who have sex with men attending a large HIV clinic in Trinidad.

Int J STD AIDS 2021 Aug 23;32(9):830-836. Epub 2021 Apr 23.

199168Medical Research Foundation of Trinidad and Tobago, Port of Spain, Trinidad.

A chart review study was conducted to determine the prevalence of syphilis and explore the associated risk factors among men who have sex with men (MSM) who attended a large HIV clinic in Trinidad during the period January-December 2019. Patients were routinely screened for syphilis annually, and demographic, clinical, and laboratory data were extracted from the medical records. Descriptive and bivariate analyses were performed, and factors significantly associated with a syphilis diagnosis were assessed using multivariate logistic regression. During the period, 218 MSM were seen, age range 19-67 years, and median age 34.0 years. The prevalence of syphilis was 41.3% (90/218), and 71.1% (64//90) of these infections were asymptomatic. Multivariate analysis using logistic regression showed that MSM living with HIV in the 30-34 years old-age group (OR, 4.32; 95% CI, 1.04-18.02), and those with a previous history of treated syphilis (OR, 10.18; 95% CI, 4.60-22.53) were more likely to be diagnosed with syphilis. The prevalence of syphilis is high among MSM attending the HIV clinic in Trinidad, and most of these infections were asymptomatic; hence, targeted and sustained interventions to reduce syphilis transmission are urgently required. Repeat episodes of syphilis may play a role in the transmission dynamics of syphilis in MSM.
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http://dx.doi.org/10.1177/0956462421997193DOI Listing
August 2021

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis.

Stroke 2021 May 20;52(5):1545-1556. Epub 2021 Apr 20.

Westmead Applied Research Centre, University of Sydney, Sydney, Australia (R.I.L.).

Background And Purpose: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.

Methods: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.

Results: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HR, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HR, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HR, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HR, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HR, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m]) subgroup (HR, 0.50 [95% CI, 0.31-0.79]).

Conclusions: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
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http://dx.doi.org/10.1161/STROKEAHA.120.031623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078131PMC
May 2021

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

Pain 2021 Apr 8. Epub 2021 Apr 8.

University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine; Department of Psychiatry; Department of Neurology; the Center for Health and Technology, Department of Neurosurgery,Rochester, NY, United States University of Washington, Department of Anesthesiology and Pain Medicine, Seattle, WA, United States Stony Brook University, Renaissance School of Medicine, Department of Anesthesiology Stony Brook, NY, United States Queens University, Kingston, Department of Anesthesiology and Perioperative Medicine, ON, Canada Formally: U.S. Food and Drug Administration, Division of Anesthesiology, Addiction Medicine, and Pain Medicine Silver Spring, MD, United States WCG, Department of Analgesic Solutions, Wayland, MA, United States Johns Hopkins School of Medicine, Department of Anesthesiology and Critical care Medicine; Department of Psychiatry and Behavioral Medicine, Baltimore, MD, United States University of California San Francisco, Departments of Anesthesia and Neurology San Francisco, CA, United States University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, PA, United States Indiana University School of Medicine, Center for Health Services and Outcomes Research, Indianapolis, IN, United States Brigham and Women's Hospital/Harvard Medical School, Department of Anesthesiology and Perioperative Medicine; Deparment of Neurology; Department of Psychiatry, Boston, MA, United States Carolinas Pain Institute, Charlotte, NC, United States Innocoll, Department of Research and Development and Medical Affairs, Athlone, Ireland American Chronic Pain Association, Rocklin, CA, United States Wake Forest School of Medicine, Department of Anesthesiology, Winston-Salem, NC, United States Southern Illinois University Edwardsville, Department of Pharmacy Practice Edwardsville, IL, United States GW Pharmaceuticals, Department of Discovery Research, Cambridge, United Kingdom Biogen, Cambridge, MA, United States University at Buffalo, Department of Sociology, Buffalo, NY, United States McGill University, Departments of Dentistry and Anesthesiology Montreal, QC, Canada MCPHS University, Department of Pharmacy Practice, Boston, MA, United States National National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States U.S. Department of Veterans Affairs/George Washington University, Washington, DC, United States Formally: Pacira, Division of Research and Development, Parsippany, NY, United States SDG LLC, Cambridge, MA, United States Sarepta, Cambridge, MA, United States Pfizer, NYC, New York, NY, United States University of Pittsburgh, Departments of Anesthesiology and Perioperative Medicine and Psychiatry, Pittsburgh, PA, United States Flexion Therapeutics, Department of Regulatory Affairs, Burlington, MA, United States.

Abstract: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.
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http://dx.doi.org/10.1097/j.pain.0000000000002283DOI Listing
April 2021

The myosin II coiled-coil domain atomic structure in its native environment.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4380;

The atomic structure of the complete myosin tail within thick filaments isolated from flight muscle is described and compared to crystal structures of recombinant, human cardiac myosin tail segments. Overall, the agreement is good with three exceptions: the proximal S2, in which the filament has heads attached but the crystal structure doesn't, and skip regions 2 and 4. At the head-tail junction, the tail α-helices are asymmetrically structured encompassing well-defined unfolding of 12 residues for one myosin tail, ∼4 residues of the other, and different degrees of α-helix unwinding for both tail α-helices, thereby providing an atomic resolution description of coiled-coil "uncoiling" at the head-tail junction. Asymmetry is observed in the nonhelical C termini; one C-terminal segment is intercalated between ribbons of myosin tails, the other apparently terminating at Skip 4 of another myosin tail. Between skip residues, crystal and filament structures agree well. Skips 1 and 3 also agree well and show the expected α-helix unwinding and coiled-coil untwisting in response to skip residue insertion. Skips 2 and 4 are different. Skip 2 is accommodated in an unusual manner through an increase in α-helix radius and corresponding reduction in rise/residue. Skip 4 remains helical in one chain, with the other chain unfolded, apparently influenced by the acidic myosin C terminus. The atomic model may shed some light on thick filament mechanosensing and is a step in understanding the complex roles that thick filaments of all species undergo during muscle contraction.
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http://dx.doi.org/10.1073/pnas.2024151118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040620PMC
April 2021

Effect of natural mutations of SARS-CoV-2 on spike structure, conformation and antigenicity.

bioRxiv 2021 Mar 15. Epub 2021 Mar 15.

New SARS-CoV-2 variants that have accumulated multiple mutations in the spike (S) glycoprotein enable increased transmission and resistance to neutralizing antibodies. Here, we study the antigenic and structural impacts of the S protein mutations from four variants, one that was involved in transmission between minks and humans, and three that rapidly spread in human populations and originated in the United Kingdom, Brazil or South Africa. All variants either retained or improved binding to the ACE2 receptor. The B.1.1.7 (UK) and B.1.1.28 (Brazil) spike variants showed reduced binding to neutralizing NTD and RBD antibodies, respectively, while the B.1.351 (SA) variant showed reduced binding to both NTD- and RBD-directed antibodies. Cryo-EM structural analyses revealed allosteric effects of the mutations on spike conformations and revealed mechanistic differences that either drive inter-species transmission or promotes viral escape from dominant neutralizing epitopes.

Highlights: Cryo-EM structures reveal changes in SARS-CoV-2 S protein during inter-species transmission or immune evasion.Adaptation to mink resulted in increased ACE2 binding and spike destabilization.B.1.1.7 S mutations reveal an intricate balance of stabilizing and destabilizing effects that impact receptor and antibody binding.E484K mutation in B.1.351 and B.1.1.28 S proteins drives immune evasion by altering RBD conformation.S protein uses different mechanisms to converge upon similar solutions for altering RBD up/down positioning.
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http://dx.doi.org/10.1101/2021.03.11.435037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986997PMC
March 2021

Non-target Site Herbicide Resistance Is Conferred by Two Distinct Mechanisms in Black-Grass ().

Front Plant Sci 2021 3;12:636652. Epub 2021 Mar 3.

Agriculture, School of Natural, and Environmental Science, Newcastle University, Newcastle upon Tyne, United Kingdom.

Non-target site resistance (NTSR) to herbicides in black-grass () results in enhanced tolerance to multiple chemistries and is widespread in Northern Europe. To help define the underpinning mechanisms of resistance, global transcriptome and biochemical analysis have been used to phenotype three NTSR black-grass populations. These comprised NTSR1 black-grass from the classic Peldon field population, which shows broad-ranging resistance to post-emergence herbicides; NTSR2 derived from herbicide-sensitive (HS) plants repeatedly selected for tolerance to pendimethalin; and NTSR3 selected from HS plants for resistance to fenoxaprop--ethyl. NTSR in weeds is commonly associated with enhanced herbicide metabolism catalyzed by glutathione transferases (GSTs) and cytochromes P450 (CYPs). As such, the NTSR populations were assessed for their ability to detoxify chlorotoluron, which is detoxified by CYPs and fenoxaprop-P-ethyl, which is acted on by GSTs. As compared with HS plants, enhanced metabolism toward both herbicides was determined in the NTSR1 and NTSR2 populations. In contrast, the NTSR3 plants showed no increased detoxification capacity, demonstrating that resistance in this population was not due to enhanced metabolism. All resistant populations showed increased levels of GSTF1, a protein functionally linked to NTSR and enhanced herbicide metabolism. Enhanced GSTF1 was associated with increased levels of the associated transcripts in the NTSR1 and NTSR2 plants, but not in NTSR3, suggestive of both pre- and post-transcriptional regulation. The related HS, NTSR2, and NTSR3 plants were subject to global transcriptome sequencing and weighted gene co-expression network analysis to identify modules of genes with coupled regulatory functions. In the NTSR2 plants, modules linked to detoxification were identified, with many similarities to the transcriptome of NTSR1 black-grass. Critical detoxification genes included members of the CYP81A family and tau and phi class GSTs. The NTSR2 transcriptome also showed network similarities to other (a)biotic stresses of plants and multidrug resistance in humans. In contrast, completely different gene networks were activated in the NTSR3 plants, showing similarity to the responses to cold, osmotic shock and fungal infection determined in cereals. Our results demonstrate that NTSR in black-grass can arise from at least two distinct mechanisms, each involving complex changes in gene regulatory networks.
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http://dx.doi.org/10.3389/fpls.2021.636652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966817PMC
March 2021

MultiPhATE2: code for functional annotation and comparison of phage genomes.

G3 (Bethesda) 2021 05;11(5)

Biosciences & Biotechnology Research Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.

To address a need for improved tools for annotation and comparative genomics of bacteriophage genomes, we developed multiPhATE2. As an extension of multiPhATE, a functional annotation code released previously, multiPhATE2 performs gene finding using multiple algorithms, compares the results of the algorithms, performs functional annotation of coding sequences, and incorporates additional search algorithms and databases to extend the search space of the original code. MultiPhATE2 performs gene matching among sets of closely related bacteriophage genomes, and uses multiprocessing to speed computations. MultiPhATE2 can be re-started at multiple points within the workflow to allow the user to examine intermediate results and adjust the subsequent computations accordingly. In addition, multiPhATE2 accommodates custom gene calls and sequence databases, again adding flexibility. MultiPhATE2 was implemented in Python 3.7 and runs as a command-line code under Linux or MAC operating systems. Full documentation is provided as a README file and a Wiki website.
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http://dx.doi.org/10.1093/g3journal/jkab074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104953PMC
May 2021

Perceived Success in Upper-Extremity Vascularized Composite Allotransplantation: A Qualitative Study.

J Hand Surg Am 2021 Mar 13. Epub 2021 Mar 13.

Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA. Electronic address:

Purpose: We performed a qualitative study to understand psychosocial factors associated with perceived success of upper-extremity vascularized composite allotransplantation (VCA). We interviewed transplant recipients and their primary caregivers.

Methods: We recruited 4 upper-extremity VCA recipients and primary caregivers for 3 of them. We conducted semistructured face-to-face interviews using a guide that explored participants' transplantation experiences. Topics included comparison of pretransplant and posttransplant expectations, reflections on factors contributing to the success of the transplant experience, and posttransplant rehabilitation and functioning. We performed a thematic analysis that produced a list of themes, subthemes, and proposed hypotheses explaining how the themes related to the study's guiding questions.

Results: Participants described several factors as contributing to the success of the transplant experience, including developing realistic expectations about posttransplant function and lifelong immunosuppression, support from one's community and particularly the primary caregiver, and framing the experience in a positive light. Social, aesthetic, and other values unique to the hands, as opposed to prosthetics, motivated recipients to undergo VCA despite its inherent risk and uncertainties.

Conclusions: Despite inherent challenges, undergoing VCA was viewed as worthwhile to regain benefits unique to hands. Participants met the challenges of the transplant process through setting realistic expectations, strong social support, and a positive perspective.

Clinical Relevance: Findings from this work may help clinicians and prospective patients to prepare for and set appropriate expectations of VCA.
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http://dx.doi.org/10.1016/j.jhsa.2021.01.001DOI Listing
March 2021

Mind-body approaches targeting the psychological aspects of opioid use problems in patients with chronic pain: evidence and opportunities.

Transl Res 2021 Aug 3;234:114-128. Epub 2021 Mar 3.

Department of Anesthesiology & Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Opioids are commonly prescribed for the management of patients with chronic noncancer pain. Despite the potential analgesic benefits of opioids, long-term opioid therapy (LTOT) may be accompanied by problems such as opioid misuse and opioid use disorder (OUD). In this review, we begin with a description of opioid misuse and OUD and the patient-specific factors associated with these problems among patients with chronic pain. We will focus primarily on highlighting the predominant role played by psychological factors in the occurrence of opioid misuse and OUD in these patients. Several psychological factors have been found to be associated with opioid use problems in patients with chronic pain, and evidence indicates that patients presenting with psychological disturbances are particularly at risk of transitioning to long-term opioid use, engaging in opioid misuse behaviors, and developing OUD. The biological factors that might underlie the association between psychological disturbances and opioid use problems in patients with chronic pain have yet to be fully elucidated, but a growing number of studies suggest that dysfunctions in reward, appetitive, autonomic, and neurocognitive systems might be involved. We end with an overview of specific types of psychological interventions that have been put forward to prevent or reduce the occurrence of opioid misuse and OUD in patients with chronic pain who are prescribed LTOT.
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http://dx.doi.org/10.1016/j.trsl.2021.02.013DOI Listing
August 2021

Modifiable Psychological Factors Affecting Functioning in Fibromyalgia.

J Clin Med 2021 Feb 17;10(4). Epub 2021 Feb 17.

Department of Anesthesiology, Harvard Medical School, Brigham & Women's Hospital, 850 Boylston St, Suite 302, Chestnut Hill, MA 02467, USA.

Objective: To examine the role of several interrelated, potentially modifiable psychological factors (i.e., mindfulness and catastrophizing) in influencing patient-reported functioning.

Methods: In this cross-sectional study, 107 patients with fibromyalgia completed self-report assessments of pain severity, functioning and impact of symptoms, mindfulness, and pain catastrophizing. Linear regression and bootstrapping mediation analyses were performed to assess the relationships between these factors.

Results: Pain intensity was significantly and positively associated with pain catastrophizing and impact of fibromyalgia on functioning. Linear regression analyses indicated that pain intensity, catastrophizing, and mindfulness affect functioning in fibromyalgia. Follow-up mediation analysis revealed a significant indirect effect of pain catastrophizing on the relationship between pain intensity and fibromyalgia functioning.

Conclusion: Individuals with fibromyalgia who have higher levels of pain and catastrophizing, and lower levels of mindfulness, are more likely to experience impaired functioning. Our findings suggest that pain catastrophizing appears to be an especially important variable contributing to reduced functioning in women with fibromyalgia. Therefore, catastrophizing-reducing treatments (e.g., cognitive behavioral therapy) are likely to have direct, beneficial impacts on functioning.
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http://dx.doi.org/10.3390/jcm10040803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922061PMC
February 2021

Same-day discharge after minimal invasive hysterectomy: Applications for improved value of care.

Eur J Obstet Gynecol Reprod Biol 2021 Apr 24;259:140-145. Epub 2021 Feb 24.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States; Magee-Womens Research Institute, Pittsburgh, PA 15213, United States; UPMC Hillman Cancer Center, Pittsburgh, PA 15232, United States; Department of Health Administration and Public Health, John G. Rangos Sr. School of Health Sciences, Duquesne University, Pittsburgh, PA 15219, United States.

Objective: Hysterectomy is one of the most common surgical procedures. Same-day discharge (SDD) is increasingly utilized for minimally invasive hysterectomies, but its uptake varies across healthcare systems and surgical specialties. An evidence-based initiative was developed to aid in the incorporation of SDD into the practice of minimally invasive hysterectomy (MIH) in the UPMC Health System. The objective of this study was to identify trends of SDD utilization across various gynecologic specialties at UPMC, as well as evaluate the impact of SDD on length of stay (LOS) and complications after the implementation of SDD initiative.

Study Design: We retrospectively identified 5554 patients who underwent MIH between 2014 and 2017 and were eligible for SDD, as determined by physicians and authorized by patients' insurance plans. Multivariable logistic regression models evaluated the trend of SDD utilization among four specialty types (general gynecologists, urogynecologists, specialized minimally invasive surgeons, and oncologists) and trends in complications. Multivariable logistic and linear regression models were applied to compare complications and LOS between patients with SDD vs. those with overnight admissions.

Results: SDD utilization increased from 28.55% to 74.99% during the study period. SDD significantly increased over the study period for all specialty types, with urogynecologists having the highest uptake from 3.9% in 2014 to 95.8% in 2017 (p<.01). After adjusting for year, specialty types, MIH procedure type, and total case time, SDD utilization was associated with shorter mean LOS (p<.01); such that mean LOS was 764.43 min (95% CI: 735.46-793.40) for SDD patients and 2041.84 min (95% CI: 2015.99-2067.70) for patients with overnight admissions. SDD was also associated with 42% lower odds (95% CI: 0.37-0.93, p=.02) of complications compared with patients with overnight admissions.

Conclusion: Same-day discharge uptake increased over years and was associated with lower odds of complications and decreased length of stay. More studies are needed to explore same-day discharge process to improve patient outcomes, patient satisfaction, and value of care.
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http://dx.doi.org/10.1016/j.ejogrb.2021.02.020DOI Listing
April 2021

Addressing Kentucky's Physician Shortage While Securing a Network for a Research-Intensive, Referral Academic Medical Center: Where Public Policy Meets Effective Clinical Strategic Planning.

Acad Med 2021 03;96(3):375-380

M. Karpf is advisor to the president and professor of internal medicine, University of Kentucky, Lexington, Kentucky.

A critical shortage of physicians is looming in the United States. The situation in Kentucky is especially dire, especially in rural areas. Class size constraints have resulted in the University of Kentucky College of Medicine (UK COM) unable to admit over 100 qualified Kentuckians each year. This article describes how leadership at University of Kentucky committed to addressing the state physician shortage while simultaneously strengthening relationships with critical partners through the establishment of two 4-year UK COM regional medical campuses. Based on criteria (such as a commitment to educating physicians, ample patients, sufficient willing physician preceptors, etc.), partners selected were Med Center Health, the leading health care system in southwestern Kentucky, and St. Elizabeth Healthcare, the predominant health care system in northern Kentucky. These regional campuses allow UK COM to expand its class size to 201 and total enrollment to 804, increasing from historically 70 to currently 120 graduates per year expected to practice in Kentucky. Critical to the success of this expansion is the buy-in of leadership and the Admissions Committee to consider students with a wider range of Medical College Admission Test scores. The regional clinical partners have substantially increased their teaching opportunities, with a greater ability to attract physicians. Both partners have made substantial financial contributions in support of the regional campuses. These relationships have energized UK COM engagement with its area alumni and have resulted in fewer Kentuckians referred out of state for advanced specialty care. Partnerships are also occurring with UK COM to increase graduate medical education offerings at the regional sites, fulfilling the vision of "training Kentuckians in Kentucky to practice in Kentucky."
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http://dx.doi.org/10.1097/ACM.0000000000003582DOI Listing
March 2021
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