Publications by authors named "Or Perlman"

4,041 Publications

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Increased Rate of New-onset Left Bundle Branch Block in Patients With Bicuspid Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation (From a National Registry).

Am J Cardiol 2021 Jul 31. Epub 2021 Jul 31.

Department of Cardiology, Rabin Medical Center, Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

There is a growing interest in transcutaneous aortic valve implantation (TAVI) therapy among patients with bicuspid severe aortic stenosis (BAV). Conduction disturbances remain a frequent complication of TAVI, and new-onset permanent LBBB (NOP-LBBB) post-TAVI may be a marker of worse outcomes. We aimed to evaluate the rate of NOP-LBBB following TAVI among patients with BAV as compared to tricuspid severe aortic stenosis (TAV). Patients enrolled in the multicenter (5 centers) Bicuspid AS TAVI Registry were reviewed and compared with patients with TAV. Patients with previous aortic valve replacement, other valve morphologies and those with preprocedural LBBB or pacemaker were excluded. NOP-LBBB was defined as LBBB first detected and persisting 30-days following TAVI. A total of 387 patients (66 with BAV, 321 with TAV), age 80.3 ± 7.3, 47% females were analyzed. The device success rates were 95% in both groups without any conversions to surgery. The rate of NOP-LBBB was significantly higher among patients with BAV versus TAV (29.2% vs 16.9%, p = 0.02). However, the rate of post procedural pacemaker implantation was similar (14.8% vs 12.5%; respectively, p = 0.62). In BAV and TAV groups, 1-year mortality (6.1% vs 7.2%; respectively, p = 0.75) and stroke rates (6.1% vs 3.5%; respectively, p = 0.30) were not significantly different. Multivariate analysis identified BAV as an independent predictor of NOP-LBBB (AdjOR = 2.7, 95%CI 1.3 to 5.4). Furthermore, BAV subtypes with raphe (type 1) were identified as independent predictors of NOP-LBBB (AdjOR = 3.2, 95%CI: 1.5 to 6.7). In conclusion, patients with BAV undergoing TAVI have greater risk for developing NOP-LBBB compared with patients with TAV and the presence of raphe was associated with increased risk of NOP-LBBB. The prognostic significance for this finding warrants further evaluation in future studies.
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http://dx.doi.org/10.1016/j.amjcard.2021.06.046DOI Listing
July 2021

Dynamics of SARS-CoV-2 Spike Proteins in Cell Entry: Control Elements in the Amino-Terminal Domains.

mBio 2021 Aug 3:e0159021. Epub 2021 Aug 3.

Department of Microbiology and Immunology, Loyola University Chicagogrid.164971.c, Maywood, Illinois, USA.

Selective pressures drive adaptive changes in the coronavirus spike proteins directing virus-cell entry. These changes are concentrated in the amino-terminal domains (NTDs) and the receptor-binding domains (RBDs) of complex modular spike protein trimers. The impact of this hypervariability on virus entry is often unclear, particularly with respect to sarbecovirus NTD variations. Therefore, we constructed indels and substitutions within hypervariable NTD regions and used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-like particles and quantitative virus-cell entry assays to elucidate spike structures controlling this initial infection stage. We identified NTD variations that increased SARS-CoV-2 spike protein-mediated membrane fusion and cell entry. Increased cell entry correlated with greater presentation of RBDs to ACE2 receptors. This revealed a significant allosteric effect, in that changes within the NTDs can orient RBDs for effective virus-cell binding. Yet, those NTD changes elevating receptor binding and membrane fusion also reduced interdomain associations, leaving spikes on virus-like particles susceptible to irreversible inactivation. These findings parallel those obtained decades ago, in which comparisons of murine coronavirus spike protein variants established inverse relationships between membrane fusion potential and virus stability. Considerable hypervariability in the SARS-CoV-2 spike protein NTDs also appear to be driven by counterbalancing pressures for effective virus-cell entry and durable extracellular virus infectivity. These forces may selectively amplify SARS-CoV-2 variants of concern. Adaptive changes that increase SARS-CoV-2 transmissibility may expand and prolong the coronavirus disease 2019 (COVID-19) pandemic. Transmission requires metastable and dynamic spike proteins that bind viruses to cells and catalyze virus-cell membrane fusion. Using newly developed assays reflecting these two essential steps in virus-cell entry, we focused on adaptive changes in SARS-CoV-2 spike proteins and found that deletions in amino-terminal domains reset spike protein metastability, rendering viruses less stable yet more poised to respond to cellular factors that prompt entry and subsequent infection. The results identify adjustable control features that balance extracellular virus stability with facile virus dynamics during cell entry. These equilibrating elements warrant attention when monitoring the evolution of pandemic coronaviruses.
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http://dx.doi.org/10.1128/mBio.01590-21DOI Listing
August 2021

Post-viral effects of COVID-19 in the olfactory system and their implications.

Lancet Neurol 2021 Jul 30. Epub 2021 Jul 30.

Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.

Background: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge.

Recent Developments: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.
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http://dx.doi.org/10.1016/S1474-4422(21)00182-4DOI Listing
July 2021

The Development of as anti-SARS-CoV-2 nanobody drug candidates.

Elife 2021 Aug 2;10. Epub 2021 Aug 2.

Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), , from a camelid nanobody phage display library. Structural data showed that bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor ACE2. The lead drug candidate possessing an Fc tag () bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of c documented an excellent stability and a high tissue bioavailability. As effective and inexpensive drug candidates, may contribute to the battle against COVID-19.
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http://dx.doi.org/10.7554/eLife.64815DOI Listing
August 2021

Longitudinal Trends and Risk Factors for Depressed Mood Among Canadian Adults During the First Wave of COVID-19.

Front Psychiatry 2021 16;12:666261. Epub 2021 Jul 16.

Department of Medicine, Université de Montréal, Centre de Recherche CHUM (Centre Hospitalier de l'Université de Montréal), Montréal, QC, Canada.

The COVID-19 pandemic has raised serious concerns about the mental health impact of people directed and indirectly affected by the virus. Because this is a rapidly evolving situation, our goal was to explore potential risk factors and trends in feelings of anxiety and depression among the general population in Canada over the first 5 months of the pandemic. We completed on-line surveys of 3,127 unique individuals representative of the Canadian general population at 4 discreet periods every 6 weeks from April 15th to July 28th 2020. We assessed feelings of anxiety, depression and loss of interest with the interRAI self-reported mood scale using a multivariable generalized estimating equation model to examine factors associated with having a 5+ score on the scale (indicating potentially depressed mood). We also investigated potential longitudinal trends to examine temporal variation in mood scores. More than 30% of participants felt highly anxious, depressed, and disinterested in everyday activities in the first survey (April), but this number decreased to about 20% over 4 months. Feeling lonely, younger age, feeling overwhelmed by one's health needs, having financial concerns, and living outside of Québec were significantly associated with depressed mood. The prevalence of depressed mood during the pandemic was between 2 and 3 times the pre-pandemic rate (especially among young people), but it can change rapidly in response to social changes. Thus, monitoring of psychological distress among vulnerable groups that may benefit from additional supports should be a priority.
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http://dx.doi.org/10.3389/fpsyt.2021.666261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322735PMC
July 2021

Binding of a pyrimidine RNA base-mimic to SARS-CoV-2 non-structural protein 9.

J Biol Chem 2021 Jul 28:101018. Epub 2021 Jul 28.

Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom. Electronic address:

The coronaviral non-structural protein 9 (Nsp9) is essential for viral replication; it is the primary substrate of Nsp12's pseudokinase domain within the viral replication transcription complex, an association that also recruits other components during different stages of RNA reproduction. In the unmodified state, Nsp9 forms an obligate homodimer via an essential GxxxG protein-interaction motif, but its ssRNA-binding mechanism remains unknown. Using structural biological techniques, here we show that a base-mimicking compound identified from a small molecule fragment screen engages Nsp9 via a tetrameric Pi-Pi stacking interaction that induces the formation of a parallel trimer-of-dimers. This oligomerization mechanism allows an interchange of "latching" N-termini, the charges of which contribute to a series of electropositive channels that suggests a potential interface for viral RNA. The identified pyrrolo-pyrimidine compound may also serve as a potential starting point for the development of compounds seeking to probe Nsp9's role within SARS-CoV-2 replication.
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http://dx.doi.org/10.1016/j.jbc.2021.101018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317483PMC
July 2021

Developmental Differences in Affective Representation Between Prefrontal and Subcortical Structures.

Soc Cogn Affect Neurosci 2021 Jul 31. Epub 2021 Jul 31.

Department of Psychology, Weiss Hall, Temple University, 1701 N 13th St. Philadelphia, PA 19122, USA.

Developmental studies have identified differences in prefrontal and subcortical affective structures between children and adults, which correspond with observed cognitive and behavioral maturations from relatively simplistic emotional experiences and expressions to more nuanced, complex ones. However, developmental changes in the neural representation of emotions have not yet been well explored. It stands to reason that adults and children may demonstrate observable differences in the representation of affect within key neurological structures implicated in affective cognition. Forty-five participants (25 children; 20 adults) passively viewed positive, negative, and neutral clips from popular films while undergoing functional magnetic resonance imaging (fMRI). Using representational similarity analysis (RSA) to measure variability in neural pattern similarity, we found developmental differences between children and adults in the amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (vmPFC), such that children generated less pattern similarity within subcortical structures relative to the vmPFC; a phenomenon not replicated among their older counterparts. Furthermore, children generated valence-specific differences in representational patterns across regions; these valence-specific patterns were not found in adults. These results may suggest that affective representations grow increasingly dissimilar over development as individuals mature from visceral affective responses to more evaluative analyses.
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http://dx.doi.org/10.1093/scan/nsab093DOI Listing
July 2021

Editorial: ML and AI Safety, Effectiveness and Explainability in Healthcare.

Front Big Data 2021 12;4:727856. Epub 2021 Jul 12.

Department of Mathematics, Queens College (CUNY), New York City, NY, United States.

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http://dx.doi.org/10.3389/fdata.2021.727856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312342PMC
July 2021

Associations of Health Conditions and Health-Related Determinants with Disability among New York City Adult Residents.

Ethn Dis 2021 15;31(3):445-452. Epub 2021 Jul 15.

Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, City University of New York, New York, NY.

Introduction: Population-based disability prevalence estimates are limited for New York City (NYC). We examined the association of several health and health-related measures with disability among NYC residents aged 20-64 years.

Methods: We used information from 1,314 adults who participated in the 2013-2014 NYC Health and Nutrition Examination Survey (HANES). We categorized survey participants as having a disability if they reported a physical, mental, and/or emotional problem preventing work or if they reported difficulty walking without special equipment because of a health problem. We used log-binomial regression to quantify the association of each exposure with disability before and after adjustment for select covariates.

Results: Overall, 12.4% of the study's NYC residents aged 20-64 years had a disability. After adjustment, disability prevalence was significantly greater among those who reported having unmet health care needs (prevalence ratio [PR] = 1.75, 95% CI: 1.18-2.57) and those who reported fair/poor general health (PR = 2.33, 95% CI: 1.68-3.24). The probability of disability was greater among NYC residents with arthritis (PR = 2.66, 95% CI: 1.85-3.98) and hypertension (PR = 1.48, 95% CI: 1.04-2.11) when compared with those without these conditions. Disability was also associated with depression (PR = 2.96, 95% CI: 2.06-4.25), anxiety (PR = 2.89, 95% CI: 2.15-3.88), and post-traumatic stress disorder (PR = 2.55, 95% CI: 1.66-3.91). Disability, however, was not associated with diabetes.

Conclusion: Disability is more prevalent among those with unmet health care needs, fair/poor general health, arthritis, hypertension, depression, anxiety, and PTSD in these NYC residents, aged 20-64 years. These findings have implications for NYC's strategic planning initiatives, which can be better targeted to groups disproportionately affected by disability.
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http://dx.doi.org/10.18865/ed.31.3.445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288469PMC
July 2021

Organizational Commitment Is Negatively Associated with Burnout Among Nephrology Nurses.

Nephrol Nurs J 2021 May-Jun;48(3):253-259

Academic Coordinator, Health Administration Track, Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

This study examines the association between burnout and organizational commitment in nephrology nurses working in hemodialysis. A cross-sectional study of all nurses working in a hospital hemodialysis unit was conducted. Low to medium level of burnout and a high level of organizational commitment were documented. A significant negative correlation was found between burnout and organizational commitment. Burnout was significantly higher among nurses who had made a career shift in the past, and lower levels of burnout were documented among married nurses. In a multivariate analysis, lower levels of burnout and a higher number of children were significantly associated with higher organizational commitment. Burnout is a negative independent predictor for organizational commitment. Inter ventions focused on reducing burnout among nurses should be implemented to improve organizational commitment.
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July 2021

A comparison of cognitive performance in the Suffolk County cohort and their unaffected siblings.

Psychiatry Res 2021 Jul 14;303:114111. Epub 2021 Jul 14.

Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.

People diagnosed with schizophrenia and other psychoses demonstrate impaired neuropsychological performance. Their unaffected siblings exhibit mild impairments relative to unrelated controls, suggesting genetic and shared environmental risk for psychosis account for some portion of cognitive impairments observed in cases. However, most sibling studies were conducted early in illness course. Studying cases and unaffected siblings later in life is valuable because diagnostic misclassification is common early in illness, possibly leading to spurious conclusions. This study compared neuropsychological performance of individuals with psychotic disorders (schizophrenia and other psychoses), their unaffected siblings, and controls. Assessments were conducted 20 years after case enrollment in the Suffolk County Mental Health Project, when siblings and controls were added to the protocol. Results showed individuals with schizophrenia and other psychoses performed worse than their matched siblings across domains. Relative to controls, siblings of participants with schizophrenia showed mild deficits in executive function and processing speed, while no significant differences were observed between siblings of those with other psychoses and controls. These findings suggest pre- and post-onset factors impact cognitive deficits in psychosis, but pre-onset factors are more salient in schizophrenia. Additionally, schizophrenia and other psychoses exist on a neurodevelopmental continuum, with schizophrenia being a more severe manifestation.
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http://dx.doi.org/10.1016/j.psychres.2021.114111DOI Listing
July 2021

Increased male live-birth rates after blastocyst-stage frozen-thawed embryo transfers compared with cleavage-stage frozen-thawed embryo transfers: a SART registry study.

F S Rep 2021 Jun 26;2(2):161-165. Epub 2021 Feb 26.

University Reproductive Associates, Hasbrouck Heights, New Jersey.

Objective: To investigate whether there is a difference in live-birth gender rates in blastocyst-stage frozen-thawed embryo transfers (FETs) compared with those in cleavage-stage FETs.

Design: Retrospective cohort study.

Setting: Academic medical center.

Patients: All women with recorded live births who underwent FET at either the blastocyst or cleavage stage, reported to the Society for Assisted Reproductive Technology during 2004-2013.

Interventions: None.

Main Outcome Measures: The primary outcome was live-birth gender rates. Demographic criteria were also collected. The chi-square analyses were used for bivariate associations, and multiple logistic regression models were used for adjusted associations, with all two-sided <.05 considered statistically significant.

Results: A statistically significant increase was noted in the number of live male births after blastocyst-stage FET compared with that after cleavage-stage FET (51.9% vs. 50.5%). After controlling for potential confounders including age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03, 1.08), body mass index (OR, 1.08; 95% CI, 1.04, 1.12), and male factor infertility (OR, 1.06; 95% CI, 1.03, 1.08), the increase in male live births after blastocyst-stage FET remained statistically significant.

Conclusions: In patients undergoing FETs, blastocyst-stage transfers are associated with higher male gender live-birth rates compared with cleavage-stage transfers.
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http://dx.doi.org/10.1016/j.xfre.2021.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267381PMC
June 2021

Early child development in low- and middle-income countries: Is it what mothers have or what they do that makes a difference to child outcomes?

Adv Child Dev Behav 2021 26;61:255-277. Epub 2021 Jun 26.

OISE, University of Toronto, Toronto, ON, Canada.

Child developmental theories and a large body of literature underscore the importance of both home and preschool influences on early childhood outcomes. We leveraged data from UNICEF'S Multiple Indicator Cluster Surveys, a nationally representative international household survey that has collected cohort comparable information on children's early development in over 118 low- and middle-income countries since 1995. We focused on data from 216,052 3- to 4-year-olds (106,037 girls) from 28 countries that had undertaken at least two surveys from 2010 to 2018. We considered the impact of maternal education and household wealth (what mothers/caregivers have) on home learning activities and sending children to early childhood programs (what mothers/caregivers do), on early child development. Our results indicated that maternal education, household wealth, home learning activities, participation in early childhood education (ECE) and scores on the early childhood development index (ECDI) generally increased over time and were significantly related to each other. Multilevel structural equation modeling revealed the mechanism through which maternal education and household wealth were associated with child outcomes. More wealthy and more educated mothers were more likely to send their child to an ECE program, which was in turn, associated with a higher ECDI score. Caregiver-reported participation in ECE had a large effect on the ECDI score while maternal education had a small effect on it. In comparison the effects of the home learning environment were much smaller. Taken together, findings suggest that education and wealth (what parents have) influence what they do (providing opportunities for learning), which in turn influences early child development. Furthermore, exposure to ECE services was particularly important for children's development. We conclude by discussing the policy implications of our findings and providing suggestions for future research.
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http://dx.doi.org/10.1016/bs.acdb.2021.04.002DOI Listing
June 2021

Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

Genome Med 2021 Jul 14;13(1):114. Epub 2021 Jul 14.

Department of Pediatrics, Emory University, Atlanta, GA, USA.

Background: Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.

Methods: We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.

Results: We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events.

Conclusions: Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.
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http://dx.doi.org/10.1186/s13073-021-00929-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281718PMC
July 2021

Development and validation of a longitudinal soft-tissue metastatic lesion matching algorithm.

Phys Med Biol 2021 Jul 30;66(15). Epub 2021 Jul 30.

School of Medicine and Public Health, Department of Medical Physics, University of Wisconsin, Madison, WI, United States of America.

Metastatic cancer presents with many, sometimes hundreds of metastatic lesions through the body, which often respond heterogeneously to treatment. Therefore, lesion-level assessment is necessary for a complete understanding of disease response. Lesion-level assessment typically requires manual matching of corresponding lesions, which is a tedious, subjective, and error-prone task. This study introduces a fully automated algorithm for matching of metastatic lesions in longitudinal medical images. The algorithm entails four steps: (1) image registration, (2) lesion dilation, (3) lesion clustering, and (4) linear assignment. In step (1), 3D deformable registration is used to register the scans. In step (2), lesion contours are conformally dilated. In step (3), lesion clustering is evaluated based on local metrics. In step (4), matching is assigned based on non-greedy cost minimization. The algorithm was optimized (e.g. choice of deformable registration algorithm, dilatation size) and validated on 140 scan-pairs of 32 metastatic cancer patients from two independent clinical trials, who received longitudinal PET/CT scans as part of their treatment response assessment. Registration error was evaluated using landmark distance. A sensitivity study was performed to evaluate the optimal lesion dilation magnitude. Lesion matching performance accuracy was evaluated for all patients and for a subset with high disease burden. Two investigated deformable registration approaches (whole body deformable and articulated deformable registrations) led to similar performance with the overall registration accuracy between 2.3 and 2.6 mm. The optimal dilation magnitude of 25 mm yielded almost a perfect matching accuracy of 0.98. No significant matching accuracy decrease was observed in the subset of patients with high lesion disease burden. In summary, lesion matching using our new algorithm was highly accurate and a significant improvement, when compared to previously established methods. The proposed method enables accurate automated metastatic lesion matching in whole-body longitudinal scans.
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http://dx.doi.org/10.1088/1361-6560/ac1457DOI Listing
July 2021

Development and validation of a longitudinal soft-tissue metastatic lesion matching algorithm.

Phys Med Biol 2021 Jul 30;66(15). Epub 2021 Jul 30.

School of Medicine and Public Health, Department of Medical Physics, University of Wisconsin, Madison, WI, United States of America.

Metastatic cancer presents with many, sometimes hundreds of metastatic lesions through the body, which often respond heterogeneously to treatment. Therefore, lesion-level assessment is necessary for a complete understanding of disease response. Lesion-level assessment typically requires manual matching of corresponding lesions, which is a tedious, subjective, and error-prone task. This study introduces a fully automated algorithm for matching of metastatic lesions in longitudinal medical images. The algorithm entails four steps: (1) image registration, (2) lesion dilation, (3) lesion clustering, and (4) linear assignment. In step (1), 3D deformable registration is used to register the scans. In step (2), lesion contours are conformally dilated. In step (3), lesion clustering is evaluated based on local metrics. In step (4), matching is assigned based on non-greedy cost minimization. The algorithm was optimized (e.g. choice of deformable registration algorithm, dilatation size) and validated on 140 scan-pairs of 32 metastatic cancer patients from two independent clinical trials, who received longitudinal PET/CT scans as part of their treatment response assessment. Registration error was evaluated using landmark distance. A sensitivity study was performed to evaluate the optimal lesion dilation magnitude. Lesion matching performance accuracy was evaluated for all patients and for a subset with high disease burden. Two investigated deformable registration approaches (whole body deformable and articulated deformable registrations) led to similar performance with the overall registration accuracy between 2.3 and 2.6 mm. The optimal dilation magnitude of 25 mm yielded almost a perfect matching accuracy of 0.98. No significant matching accuracy decrease was observed in the subset of patients with high lesion disease burden. In summary, lesion matching using our new algorithm was highly accurate and a significant improvement, when compared to previously established methods. The proposed method enables accurate automated metastatic lesion matching in whole-body longitudinal scans.
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http://dx.doi.org/10.1088/1361-6560/ac1457DOI Listing
July 2021

Physician Satisfaction With Telemedicine During the COVID-19 Pandemic: The Mayo Clinic Florida Experience.

Mayo Clin Proc Innov Qual Outcomes 2021 Aug 1;5(4):771-782. Epub 2021 Jul 1.

Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL.

Objective: To evaluate physician perceptions and attitudes toward telemedicine use at a tertiary care academic institution in northeast Florida during the coronavirus disease 2019 pandemic.

Patients And Methods: An anonymous 38-question cross-sectional survey was developed using Qualtrics survey software (Qualtrics) and e-mailed to all staff physicians from all specialty disciplines at Mayo Clinic in Florida. The survey was open from August 17, 2020, through September 1, 2020. Collected data included general demographic characteristics and employment information, attitude and experience with telemedicine use before and during the coronavirus disease 2019 pandemic, perception of patients' experience, and the effect of telemedicine on burnout.

Results: The survey was distributed to 529 eligible physicians at our institution, with 103 physicians responding (20%). The distribution of specialties was 22% primary care specialties, 41% other internal medicine subspecialties, and 18% surgical specialties. Collectively, 63% found comparable quality of care when provided virtually (vs in-person) whereas 80% perceived telemedicine as cost-effective. A total of 76% of physicians felt that telemedicine increased flexibility and control over patient care activities, with 36% reporting improved work-life balance and 30% reporting improved burnout symptoms. Overall, 42% preferred using telemedicine over in-person visits when possible.

Conclusion: Physicians generally had positive attitudes regarding the adoption of telemedicine and perceived that the quality of health care delivery as generally comparable to in-person care. Future studies are needed to explore attitudes regarding telemedicine after the pandemic and how this virtual technology may be further used to improve physicians' professional and personal well-being.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245346PMC
August 2021

Targeted long-read sequencing identifies missing disease-causing variation.

Am J Hum Genet 2021 Jun 25. Epub 2021 Jun 25.

Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.006DOI Listing
June 2021

Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.

J Med Chem 2021 07 2;64(14):10047-10058. Epub 2021 Jul 2.

Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States.

A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276672PMC
July 2021

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.

Proc Natl Acad Sci U S A 2021 07;118(29)

Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506;

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.
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http://dx.doi.org/10.1073/pnas.2101555118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307543PMC
July 2021

Initial Experience With Low-Dose 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging With Deep Learning Enhancement.

J Comput Assist Tomogr 2021 Jun 26. Epub 2021 Jun 26.

From the Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI Department of Radiology, Penn State Health, Hershey, PA Department of Medical Physics, University of Wisconsin-Madison, Madison, WI.

Objective: To demonstrate the utility of deep learning enhancement (DLE) to achieve diagnostic quality low-dose positron emission tomography (PET)/magnetic resonance (MR) imaging.

Methods: Twenty subjects with known Crohn disease underwent simultaneous PET/MR imaging after intravenous administration of approximately 185 MBq of 18F-fluorodeoxyglucose (FDG). Five image sets were generated: (1) standard-of-care (reference), (2) low-dose (ie, using 20% of PET counts), (3) DLE-enhanced low-dose using PET data as input, (4) DLE-enhanced low-dose using PET and MR data as input, and (5) DLE-enhanced using no PET data input. Image sets were evaluated by both quantitative metrics and qualitatively by expert readers.

Results: Although low-dose images (series 2) and images with no PET data input (series 5) were nondiagnostic, DLE of the low-dose images (series 3 and 4) achieved diagnostic quality images that scored more favorably than reference (series 1), both qualitatively and quantitatively.

Conclusions: Deep learning enhancement has the potential to enable a 90% reduction of radiotracer while achieving diagnostic quality images.
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http://dx.doi.org/10.1097/RCT.0000000000001174DOI Listing
June 2021

Middle East respiratory syndrome coronavirus - The need for global proactive surveillance, sequencing and modeling.

Travel Med Infect Dis 2021 Jun 16;43:102118. Epub 2021 Jun 16.

Department of Infection, Division of Infection and Immunity, University College London and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2021.102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205546PMC
June 2021

Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity.

Sci Adv 2021 06 16;7(25). Epub 2021 Jun 16.

State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.
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http://dx.doi.org/10.1126/sciadv.abf8577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208716PMC
June 2021

Intrapartum ultrasound for the management of the active pushing phase.

Am J Obstet Gynecol MFM 2021 Jun 11:100422. Epub 2021 Jun 11.

Ultrasound Unit, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

The anxiety and anticipation that accompany pregnancy, labor, and delivery may be relieved by education, providing knowledge regarding the physiological process of childbirth. Intrapartum ultrasound is an available, simple, intuitive, real-time tool that enables visualization of the fetal head within the birth canal. Both the attending staff and expectant parent can assess its movements and descent in response to the pushing efforts during the active pushing phase. This review described the potential obstetrical and psychological advantages of intrapartum ultrasound in managing the active pushing phase.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100422DOI Listing
June 2021

A nationwide analysis of population group differences in the COVID-19 epidemic in Israel, February 2020-February 2021.

Lancet Reg Health Eur 2021 Aug 5;7:100130. Epub 2021 Jun 5.

Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6139001, Israel.

Background: Social inequalities affect the COVID-19 burden and vaccine uptake. The aim of this study was to explore inequalities in the incidence and mortality rate of SARS-CoV-2 infection and vaccine uptake in various sociodemographic and population group strata in Israel.

Methods: We analysed nationwide publicly available, aggregated data on PCR-confirmed SARS-CoV-2 infections and COVID-19 deaths between March 2020 and February 2021, as well as the first three months of COVID-19 immunisation according to sociodemographics, including population group and residential socioeconomic status (SES). We computed incidence and mortality rates of COVID-19. Comparisons between towns with predominantly Arab, ultra-Orthodox Jewish (the minorities), general Jewish populations, and according to SES, were conducted using generalised linear models with negative binomial distribution.

Findings: Overall, 774,030 individuals had SARS-CoV-2 infection (cumulative incidence 84•5 per 1,000 persons) and 5687 COVID-19 patients had died (mortality rate 62•8 per 100,000 persons). The highest mortality rate was found amongst the elderly. Most (>75%) individuals aged 60 years or above have been vaccinated with BNT162b2 vaccine. The risk of SARS-CoV-2 infection was higher in towns with predominantly Arab and ultra-Orthodox Jewish populations than in the general Jewish population, and in low SES communities. COVID-19 mortality rate was highest amongst Arabs. Conversely, vaccine uptake was lower amongst Arab and ultra-Orthodox Jewish populations and low SES communities.

Interpretation: Ethnic and religious minorities and low SES communities experience substantial COVID-19 burden, and have lower vaccine uptake, even in a society with universal accessibility to healthcare. Quantifying these inequalities is fundamental towards reducing these gaps, which imposes a designated apportion of resources to adequately control the pandemic.

Funding: No external funding was available for this study.
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http://dx.doi.org/10.1016/j.lanepe.2021.100130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177966PMC
August 2021

A Versatile Human Intestinal Organoid-Derived Epithelial Monolayer Model for the Study of Enteric Pathogens.

Microbiol Spectr 2021 Jun 9:e0000321. Epub 2021 Jun 9.

Mucosal Immunology and Biology Research Center, Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston, Massachusetts, USA.

Gastrointestinal infections cause significant morbidity and mortality worldwide. The complexity of human biology and limited insights into host-specific infection mechanisms are key barriers to current therapeutic development. Here, we demonstrate that two-dimensional epithelial monolayers derived from human intestinal organoids, combined with like bacterial culturing conditions, provide significant advancements for the study of enteropathogens. Monolayers from the terminal ileum, cecum, and ascending colon recapitulated the composition of the gastrointestinal epithelium, in which several techniques were used to detect the presence of enterocytes, mucus-producing goblet cells, and other cell types following differentiation. Importantly, the addition of receptor activator of nuclear factor kappa-B ligand (RANKL) increased the presence of M cells, critical antigen-sampling cells often exploited by enteric pathogens. For infections, bacteria were grown under like conditions known to induce virulence. Overall, interesting patterns of tissue tropism and clinical manifestations were observed. Shigella flexneri adhered efficiently to the cecum and colon; however, invasion in the colon was best following RANKL treatment. Both Salmonella enterica serovars Typhi and Typhimurium displayed different infection patterns, with . Typhimurium causing more destruction of the terminal ileum and . Typhi infecting the cecum more efficiently than the ileum, particularly with regard to adherence. Finally, various pathovars of Escherichia coli validated the model by confirming only adherence was observed with these strains. This work demonstrates that the combination of human-derived tissue with targeted bacterial growth conditions enables powerful analyses of human-specific infections that could lead to important insights into pathogenesis and accelerate future vaccine development. While traditional laboratory techniques and animal models have provided valuable knowledge in discerning virulence mechanisms of enteric pathogens, the complexity of the human gastrointestinal tract has hindered our understanding of physiologically relevant, human-specific interactions; and thus, has significantly delayed successful vaccine development. The human intestinal organoid-derived epithelial monolayer (HIODEM) model closely recapitulates the diverse cell populations of the intestine, allowing for the study of human-specific infections. Differentiation conditions permit the expansion of various cell populations, including M cells that are vital to immune recognition and the establishment of infection by some bacteria. We provide details of reproducible culture methods and infection conditions for the analyses of , , and pathogenic Escherichia coli in which tissue tropism and pathogen-specific infection patterns were detected. This system will be vital for future studies that explore infection conditions, health status, or epigenetic differences and will serve as a novel screening platform for therapeutic development.
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http://dx.doi.org/10.1128/Spectrum.00003-21DOI Listing
June 2021
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