Poor Oral Health Is Associated With Inflammation, Aortic Valve Calcification, and Brain Volume Among Forager-Farmers.

Poor oral health is associated with cardiovascular disease and dementia. Potential pathways include sepsis from oral bacteria, systemic inflammation, and nutritional deficiencies. However, in post-industrialized populations, links between oral health and chronic disease may be confounded because the lower socioeconomic exposome (poor diet, pollution, and low physical activity) often entails insufficient dental care. We assessed tooth loss, caries, and damaged teeth, in relation to cardiovascular and brain aging among the Tsimane, a subsistence population living a relatively traditional forager-horticulturalist lifestyle with poor dental health, but minimal cardiovascular disease and dementia. Dental health was assessed by a physician in 739 participants aged 40-92 years with cardiac and brain health measured by chest computed tomography (CT; n = 728) and brain CT (n = 605). A subset of 356 individuals aged 60+ were also assessed for dementia and mild cognitive impairment (n = 33 impaired). Tooth loss was highly prevalent, with 2.2 teeth lost per decade and a 2-fold greater loss in women. The number of teeth with exposed pulp was associated with higher inflammation, as measured by cytokine levels and white blood cell counts, and lower body mass index. Coronary artery calcium and thoracic aortic calcium were not associated with tooth loss or damaged teeth. However, aortic valve calcification and brain tissue loss were higher in those who had more teeth with exposed pulp. Overall, these results suggest that dental health is associated with indicators of chronic diseases in the absence of typical confounds, even in a population with low cardiovascular and dementia risk factors.

Safety and tolerability of tedizolid as oral treatment for bone and joint infections.

Bone and joint infections (BJIs) are common infections increasingly managed with oral therapy. However, there are limited safe oral options for many Gram-positive pathogens. In animal studies and short-term human use, tedizolid lacks the hematologic and neurologic toxicity of the other available oxazolidinone, linezolid. However, there are limited prospective safety data. We conducted an open-label, non-comparative trial of oral tedizolid for BJI treatment. Primary outcomes were safety and cure rate. Eligible patients had a BJI caused by documented or suspected Gram-positive pathogen, required 4-12 weeks of therapy, and did not have myelosuppression or peripheral/optic neuropathy. Subjects underwent weekly evaluation for cytopenias and neuropathy. We enrolled 44 subjects; five were lost to follow-up. Two subjects did not complete planned treatment because of rash (n = 1) and urgent surgery (n = 1). Of 37 patients with evaluable outcomes, 17 (46%) had hardware-associated infection, 13 (35%) had osteomyelitis, 5 (14%) had prosthetic joint infection, and 2 (5%) had other BJIs. Median (mean, range) treatment duration was 12 (10.1, 4-12) weeks. There were no cases of cytopenias or peripheral or optic neuropathy. Treatment cure occurred in 13 (35%); 19 (51%) required antibiotic continuation after 12 weeks of tedizolid related to retained hardware at the BJI site, and failure occurred in four (11%), two unlikely, one possibly, and one probably due to tedizolid. We found that oral tedizolid was well tolerated for prolonged BJI treatment without significant toxicity. Clinical failure rate was similar to that of other published BJI investigations. (This study has been registered at Clinicaltrials.gov under identifier NCT03009045.) IMPORTANCE Bone and joint infections are common infections with limited effective and safe oral options for Gram-positive infections. The largest prospective clinical trial of tedizolid therapy for bone and joint infections enrolled 44 patients and tested each in person weekly with detailed safety monitoring including tests for leukopenia, anemia, thrombocytopenia, peripheral neuropathy, and optic neuropathy for up to 12 weeks. Findings demonstrated tedizolid was generally well tolerated and there were no incident cases of cytopenias or neuropathy. Cure rates were similar to that in other bone and joint infection studies. In summary, oral tedizolid appears to be a well-tolerated oral option for Gram-positive bone and joint infections.

The relationship between left ventricular dilation and right ventricular diastolic function in children with a patent ductus arteriosus.

The impact of a dilated left ventricular (LV) on right ventricular (RV) diastolic function has not been investigated. We hypothesized that in patients with a patent ductus arteriosus (PDA), LV dilation causes elevation of the RV end-diastolic pressure (RVEDP) through ventricular-ventricular interaction. We identified patients' ages 6 months to 18 years who underwent transcatheter PDA closure at our center from 2010 to 2019. One hundred and thirteen patients were included with a median age of 3 years (0.5-18). The median LV end-diastolic dimension (LVEDD) Z-score was 1.6 (-1.4-6.3). RVEDP was positively associated with RV systolic pressure (0.38, P < 0.01), ratio of pulmonary artery/aortic systolic pressure (0.4, P < 0.01), and pulmonary capillary wedge pressure (0.71, P < 0.01). RVEDP was not associated with LVEDD Z-score (0.03, P = 0.74). In children with a PDA, RVEDP was not associated with LV dilation, but was positively associated with RV systolic pressure.

Social and structural determinants of COVID-19 vaccine uptake among racial and ethnic groups.

Latino, Black, American Indian/Alaska Native (AI/AN), and Native Hawaiian or Other Pacific Islander people have the highest hospitalizations and death rates from COVID-19. Social inequalities have exacerbated COVID-19 related health disparities. This study examines social and structural determinants of COVID-19 vaccine uptake. Results from logistic regressions suggest Latino and Black people were less likely to be vaccinated. People that did not have health insurance, a primary care doctor and were unemployed were more than 30% less likely to be vaccinated for COVID-19. Greater perceived health inequalities in one's neighborhood and perceived racial/ethnic discrimination were associated with a decreased odds in being vaccinated. People that suffered the loss of a household member from COVID-19 were three times more likely to have been vaccinated. Establishing policies that will increase access to health insurance and create jobs with living wages may have lasting impacts. Furthermore, collaboration with local and national community organizations can enhance the development of sustainable solutions.

Eating and Drinking Narratives in Biblical-Rabbinic Versus Graeco-Roman Writings.

The writings of ancient Greece and Rome and of biblical Israel are filled with descriptions of food. The narratives in Greek and Roman mythology and poetry often describe violent and repulsive behavior associated with food. The biblical narratives, in contrast, tend to view food in a respectful and purposeful manner. We compare and contrast some of these stories with regard to the specific themes: restraint, respect, purpose, and order. In each comparison, patterns of eating described in biblical laws and narratives will be contrasted with those emerging from Graeco-Roman stories and customs.

Changes in left ventricular systolic function after transcatheter patent ductus arteriosus closure in premature infants.

Background: Changes in left ventricular (LV) systolic function have not been well described in premature neonates after transcatheter patent ductus arteriosus (PDA) closure. Methods and Results: We retrospectively identified all premature neonates < 3 kg who underwent a transcatheter PDA closure at our center between January 1 2015 and January 31, 2021. LV indices before and after closure were extracted and an analysis was performed. Overall, 23 neonates were included with a mean procedural weight of 1894 ± 622 g. At 24 h after closure, the median left ventricular ejection fraction (LVEF) (66% interquartile range [IQR] 12% vs. 61% IQR 12, P< 0.001) and median LV end-diastolic dimension z-score (3.3 IQR 1.8 vs. 1.4 IQR 2.6, P < 0.001) both decreased and 5 (22%) neonates had an LVEF <55%. Patients who had an LVEF <55% at 24 h had a higher preprocedure LV end-diastolic dimension z-score (4.2 IQR 1.2 vs. 2.8 IQR 1.6, P = 0.01), a higher preprocedure LV end-diastolic volume (19 mL IQR 4 mL vs. 11 mL IQR 11, P = 0.03), a higher birth weight (940 g IQR 100 g vs. 760 g IQR 140, P = 0.04), and were more likely to receive intravenous calcium during the procedure (60% vs. 11%, P = 0.04) compared to those with an LVEF ≥55% at 24 h after closure. Of those with LVEF <55% at 24 h, all normalized before discharge. Conclusion: In preterm neonates who underwent successful transcatheter PDA closure, 23% developed abnormal LVEF after closure and those with significant LV dilation before the procedure were at increased risk for the development of LVEF <55% after closure.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

Large Scale SARS-CoV-2 Molecular Testing and Genomic Surveillance Reveal Prolonged Infections, Protracted RNA shedding, and Viral Reinfections.

Large-scale SARS-CoV-2 molecular testing coupled with whole genome sequencing in the diagnostic laboratories is instrumental for real-time genomic surveillance. The extensive genomic, laboratory, and clinical data provide a valuable resource for understanding cases of reinfection versus prolonged RNA shedding and protracted infections. In this study, data from a total of 22,292 clinical specimens, positive by SARS-CoV-2 molecular diagnosis at Johns Hopkins clinical virology laboratory between March 11th 2020 to September 23rd 2021, were used to identify patients with two or more positive results. A total of 3,650 samples collected from 1,529 patients who had between 2 and 20 positive results were identified in a time frame that extended up to 403 days from the first positive. Cycle threshold values (Ct) were available for 1,622 samples, the median of which was over 30 by 11 days after the first positive. Extended recovery of infectious virus on cell culture was notable for up to 70 days after the first positive in immunocompromised patients. Whole genome sequencing data generated as a part of our SARS-CoV-2 genomic surveillance was available for 1,027 samples from patients that had multiple positive tests. Positive samples collected more than 10 days after initial positive with high quality sequences (coverage >90% and mean depth >100), were more likely to be from unvaccinated, or immunosuppressed patients. Reinfections with viral variants of concern were found in 3 patients more than 130 days from prior infections with a different viral clade. In 75 patients that had 2 or more high quality sequences, the acquisition of more substitutions or deletions was associated with lack of vaccination and longer time between the recovered viruses. Our study highlights the value of integrating genomic, laboratory, and clinical data for understanding the biology of SARS-CoV-2 as well as for setting a precedent for future epidemics and pandemics.

Identifying key components of a web-based long term care planning intervention for family caregivers of individuals with intellectual/developmental disabilities.

BACKGROUND: Few family caregivers of individuals with intellectual or developmental disabilities develop long-term care (LTC) plans for their relative. Web-based interventions promoting LTC planning have potential for widespread adoption into clinical practice. METHODS: We conducted focus groups with 49 primary caregivers of individuals with intellectual or developmental disabilities in NY, PA, OH, DE, and TX to identify barriers and facilitators of LTC planning, review existing tools, and identify critical features for web-based LTC planning interventions. Participants also answered questions on demographic characteristics and functional status. RESULTS: NVivo qualitative analysis software was used to analyse focus groups using a grounded theory approach. Caregivers identified web tool accessibility and topics such as finances, housing, and government benefits as critical. Caregivers also described desired features for a LTC planning tool. CONCLUSIONS: This study identified desired characteristics of web-based LTC planning tools and ways in which existing web-based interventions might be adapted or enhanced.

Clinical Validation of the Xpert MTB/RIF Test for Identification of the Mycobacterium tuberculosis Complex in Acid-Fast Bacillus Smear-Positive MGIT Broth Cultures.

The identification of the Mycobacterium tuberculosis complex (MTBC) from smear-positive broth cultures can be achieved using several methods, including both lab-developed and commercially available molecular assays. In the United States, a commercially available probe-based assay has been used for over a decade by many laboratories for identification of MTBC directly from acid-fast bacilli (AFB) smear-positive broth cultures, including those recovered from the MGIT 960 system. However, recent difficulties in obtaining probe kits for identification resulted in mycobacteriology laboratories looking for alternative platforms to provide for rapid identification of MTBC and detection of rifampin resistance. The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA) has shown high sensitivity for the diagnosis of MTBC from pulmonary specimens but is not often used for identification directly from smear-positive MGIT 960 broth cultures (Becton, Dickinson, Sparks, MD). We sought to validate the Xpert MTB/RIF test for use with AFB smear-positive MGIT 960 cultures in a clinical hospital setting. Overall, the assay showed a categorical agreement of 100% for identification of MTBC and detection of rifampin resistance. No false-positive results or cross-reactivity were noted. Findings indicate that the Xpert MTB/RIF test may be suitable as a rapid replacement for identification of MTBC and detection of rifampin resistance from AFB smear-positive MGIT 960 broth cultures.

Body mass index and age are associated with ventricular end-diastolic pressure in adults with a Fontan circulation.

INTRODUCTION: Systemic ventricular end-diastolic pressure is an important haemodynamic variable in adult patients with Fontan circulation. Risk factors associated with elevated end-diastolic pressure have not been clearly identified in this population. METHODS: All patients > 18 years with Fontan circulation who underwent cardiac catheterisation at our centre between 1/08 and 3/19 were included. Relevant patient variables were extracted. Univariate and multivariate general linear models were analysed to identify variables associated with end-diastolic pressure. RESULTS: Forty-two patients were included. Median age was 24.0 years (20.9-29.0) with a body mass index of 23.7 kg/m2 (21.5-29.7). 10 (23.8%) patients had a systemic right ventricle. The median (Interquartile range) and mean pulmonary artery pressure were 11.0 mmHg (9.0-12.0) and 16.0 mmHg (13.0-18.0), respectively. On univariate analysis, end-diastolic pressure was positively associated with body mass index (p < 0.01), age > 25 years (p = 0.04), symptoms of heart failure (p < 0.01), systemic ventricular systolic pressure (p = 0.03), pulmonary artery mean pressure (p < 0.01), and taking diuretics (p < 0.01) or sildenafil (p < 0.01). End-diastolic pressure was negatively associated with aortic saturation (p < 0.01). On multivariate analysis, end-diastolic pressure was positively associated with age ≥ 25 years (p < 0.01), and body mass index (p = 0.04). CONCLUSIONS: In a cohort of adult patients with Fontan circulation undergoing catheterisation, end-diastolic pressure was positively associated with age ≥ 25 years and body mass index on multivariate analysis. Maintaining a healthy body mass index may offer haemodynamic benefit in adults with Fontan physiology.

Effect of Superstitious Beliefs and Risk Intuitions on Genetic Test Decisions.

INTRODUCTION: Moving beyond numeric representations of risk perceptions, we examine cognitive causation, or superstitious thinking, and negative affect in risk as predictors of MC1R (i.e., moderate v. high risk) skin cancer genetic testing and responses to this testing. METHODS: Participants (N = 496) completed baseline assessments using validated measures of cognitive causation (beliefs that thinking about cancer risk increases cancer likelihood) and negative affect in risk (negative feelings generated during risk perception) and subsequently received a test offer. Participants could access a website to learn about and request genetic testing. Those who tested (n = 167) completed assessments of cognitive and affective reactions 2 wk after testing, including the Impact of Events-Revised Intrusive thoughts subscale. RESULTS: Those with higher negative affect in risk were less likely to return a saliva sample for testing (odds ratio = 0.98, 95% confidence interval = 0.96-0.99). Those with higher cognitive causation reported more fear (b = 0.28-0.31; P's < 0.05). Higher negative affect in risk was associated with more emotion-laden test responses, particularly in those receiving higher-risk as compared with average-risk results. CONCLUSION: Negative affect in risk did not hamper test information seeking, although it did inhibit the uptake of genetic testing. Those with higher cognitive causation showed more fear regarding their test result, as indicated by higher distress in those who received average-risk results and lower believability in those who received higher-risk results.

An Update on Severe Acute Respiratory Syndrome Coronavirus 2 Diversity in the US National Capital Region: Evolution of Novel and Variants of Concern.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants concerning for enhanced transmission, evasion of immune responses, or associated with severe disease have motivated the global increase in genomic surveillance. In the current study, large-scale whole-genome sequencing was performed between November 2020 and the end of March 2021 to provide a phylodynamic analysis of circulating variants over time. In addition, we compared the viral genomic features of March 2020 and March 2021. METHODS: A total of 1600 complete SARS-CoV-2 genomes were analyzed. Genomic analysis was associated with laboratory diagnostic volumes and positivity rates, in addition to an analysis of the association of selected variants of concern/variants of interest with disease severity and outcomes. Our real-time surveillance features a cohort of specimens from patients who tested positive for SARS-CoV-2 after completion of vaccination. RESULTS: Our data showed genomic diversity over time that was not limited to the spike sequence. A significant increase in the B.1.1.7 lineage (alpha variant) in March 2021 as well as a transient circulation of regional variants that carried both the concerning S: E484K and S: P681H substitutions were noted. Lineage B.1.243 was significantly associated with intensive care unit admission and mortality. Genomes recovered from fully vaccinated individuals represented the predominant lineages circulating at specimen collection time, and people with those infections recovered with no hospitalizations. CONCLUSIONS: Our results emphasize the importance of genomic surveillance coupled with laboratory, clinical, and metadata analysis for a better understanding of the dynamics of viral spread and evolution.

Comprehension of skin cancer genetic risk feedback in primary care patients.

Few studies have examined comprehension and miscomprehension of genetic risk feedback for moderate-risk genes in the general population. We examined the prevalence and nature of accurate and inaccurate genetic risk feedback comprehension among those who received genetic testing for melanocortin-1-receptor (MC1R) gene variants that confer moderate melanoma risk. Participants (N = 145 Albuquerque, NM) were tested as part of a randomized controlled trial. Two weeks after receiving MC1R genetic risk feedback, participants answered open-ended questions regarding their reactions to the MC1R feedback report. Participants' comprehension of their feedback (average-risk or higher-risk for melanoma) was evaluated through qualitative analysis of open-ended responses. Most participants demonstrated comprehension of their feedback results (i.e., 63% of average-risk participants [ARPs]; 51% of higher-risk participants [HRPs]). Miscomprehension was evident in fewer participants (i.e., 16% of ARPs, 11% of HRPs). A few ARPs misunderstood the purpose of testing, whereas a few HRPs reported confusion about the meaning of their risk feedback. Some participants' responses to the open-ended questions were too ambiguous to ascertain comprehension or miscomprehension (i.e., 21% of ARPs, 38% of HRPs). Taken together, these findings suggest that genetic testing feedback for MC1R risk variants is largely comprehensible to general population participants. This study adds to the work examining comprehension and usage of common, moderate risk genetic information in public health contexts. However, to maximize the utility of genetic risk information in the general population, further research is needed to investigate and address areas where common genetic risk feedback misunderstandings occur.

Infection With the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta Variant Is Associated With Higher Recovery of Infectious Virus Compared to the Alpha Variant in Both Unvaccinated and Vaccinated Individuals.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) B.1.617.2 (Delta) displaced B.1.1.7 (Alpha) and is associated with increases in coronavirus disease 2019 (COVID-19) cases, greater transmissibility, and higher viral RNA loads, but data are lacking regarding the infectious virus load and antiviral antibody levels in the nasal tract. METHODS: Whole genome sequencing, cycle threshold (Ct) values, infectious virus, anti-SARS-CoV-2 immunoglobulin G (IgG) levels, and clinical chart reviews were combined to characterize SARS-CoV-2 lineages circulating in the National Capital Region between January and September 2021 and differentiate infections in vaccinated and unvaccinated individuals by the Delta, Alpha, and B.1.2 (the predominant lineage prior to Alpha) variants. RESULTS: The Delta variant displaced the Alpha variant to constitute 99% of the circulating lineages in the National Capital Region by August 2021. In Delta infections, 28.5% were breakthrough cases in fully vaccinated individuals compared to 4% in the Alpha infected cohort. Breakthrough infections in both cohorts were associated with comorbidities, but only Delta infections were associated with a significant increase in the median days after vaccination. More than 74% of Delta samples had infectious virus compared to <30% from the Alpha cohort. The recovery of infectious virus with both variants was associated with low levels of local SARS-CoV-2 IgG. CONCLUSIONS: Infection with the Delta variant was associated with more frequent recovery of infectious virus in vaccinated and unvaccinated individuals compared to the Alpha variant but was not associated with an increase in disease severity in fully vaccinated individuals. Infectious virus was correlated with the presence of low amounts of antiviral IgG in the nasal specimens.

High-efficiency CRISPR gene editing in C. elegans using Cas9 integrated into the genome.

Gene editing in C. elegans using plasmid-based CRISPR reagents requires microinjection of many animals to produce a single edit. Germline silencing of plasmid-borne Cas9 is a major cause of inefficient editing. Here, we present a set of C. elegans strains that constitutively express Cas9 in the germline from an integrated transgene. These strains markedly improve the success rate for plasmid-based CRISPR edits. For simple, short homology arm GFP insertions, 50-100% of injected animals typically produce edited progeny, depending on the target locus. Template-guided editing from an extrachromosomal array is maintained over multiple generations. We have built strains with the Cas9 transgene on multiple chromosomes. Additionally, each Cas9 locus also contains a heatshock-driven Cre recombinase for selectable marker removal and a bright fluorescence marker for easy outcrossing. These integrated Cas9 strains greatly reduce the workload for producing individual genome edits.

"Let's Talk about Skin Cancer": Examining Association between Family Communication about Skin Cancer, Perceived Risk, and Sun Protection Behaviors.

Family communication about skin cancer risk may motivate protective behaviors. However, it is unclear how widespread such communication might be. In this study, we describe prevalence and patterns (across environmental, personal, and behavioral factors) of family communication about skin cancer across N = 600 diverse (79% female, 48% Hispanic, 44% non-Hispanic White) primary care patients from Albuquerque, New Mexico, a geographical location with year-round sun exposure. Over half reported discussing general cancer (77%) and skin cancer risks (66%) with their families. The most frequent target of skin cancer risk communication included doctors (54%), followed by friends/coworkers (49%), spouse/partner (43%), other family members (38%), sisters (36%), mothers (36%), daughters (33%), sons (32%), father (24%), and brothers (22%). On average, participants reported having talked to three family members about skin cancer risks. The most frequently discussed content of skin cancer risk communication was the use of sun protection (89%), followed by the personal risk of skin cancer (68%), who had skin cancer in the family (60%), family risk of skin cancer (59%), time of sun exposure (57%), and skin cancer screening (57%). A family or personal history of cancer, higher perceived risk, higher health literacy, being non-Hispanic, having higher education or income, and proactive sun protective behavior were associated with greater family communication about general cancer and skin cancer risks. These study findings have implications for interventions that encourage discussions about skin cancer risk, sun protection, and skin cancer screening that lead to adoption of sun-safe behaviors.