Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension.

RATIONALE: Idiopathic Pulmonary Arterial Hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling due to plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. OBJECTIVE: Test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. METHODS: We used digital spatial transcriptomics to profile the genome-wide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n= 11) and compared these data to the intima+media and adventitia of control pulmonary artery (n=5). RESULTS: We detected 8273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima-media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for (i) genes associated with TGFß-signaling and (ii) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and interferon signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. CONCLUSIONS: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.

Inner Ear Breaches from Vestibular Schwannoma Surgery: Revisiting the Incidence of Otologic Injury from Retrosigmoid and Middle Cranial Fossa Approaches.

OBJECTIVE: To assess the rate of iatrogenic injury to the inner ear in vestibular schwannoma resections. STUDY DESIGN: Retrospective case review. SETTING: Multiple academic tertiary care hospitals. PATIENTS: Patients who underwent retrosigmoid or middle cranial fossa approaches for vestibular schwannoma resection between 1993 and 2015. INTERVENTION: Diagnostic with therapeutic implications. MAIN OUTCOME MEASURE: Drilling breach of the inner ear as confirmed by operative note or postoperative computed tomography (CT). RESULTS: 21.5% of patients undergoing either retrosigmoid or middle fossa approaches to the internal auditory canal were identified with a breach of the vestibulocochlear system. Because of the lack of postoperative CT imaging in this cohort, this is likely an underestimation of the true incidence of inner ear breaches. Of all postoperative CT scans reviewed, 51.8% had an inner ear breach. As there may be bias in patients undergoing postoperative CT, a middle figure based on sensitivity analyses estimates the incidence of inner ear breaches from lateral skull base surgery to be 34.7%. CONCLUSIONS: A high percentage of vestibular schwannoma surgeries via retrosigmoid and middle cranial fossa approaches result in drilling breaches of the inner ear. This study reinforces the value of preoperative image analysis for determining risk of inner ear breaches during vestibular schwannoma surgery and the importance of acquiring CT studies postoperatively to evaluate the integrity of the inner ear.

An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction.

Adeno-associated virus (AAV) vectors are currently the most efficient option for intracranial gene therapies to treat neurodegenerative disease. Increased efficacy and safety will depend upon robust and specific expression of therapeutic genes into target cell-types within the human brain. In this study, we set out with two objectives: (1) to identify capsids with broader transduction of the striatum upon intracranial injection in mice and (2) to test a truncated human choline acetyltransferase (ChAT) promoter that would allow efficient and selective transduction of cholinergic neurons. We compared AAV9 and an engineered capsid, AAV-S, to mediate widespread reporter gene expression throughout the striatum. We observed that AAV-S transduced a significantly greater area of the injected hemisphere primarily in the rostral direction compared with AAV9 (CAG promoter). We tested AAV9 vectors packaging a reporter gene expression cassette driven by either the ChAT or CAG promoter. Specificity of transgene expression of ChAT neurons over other cells was 7-fold higher, and efficiency was 3-fold higher for the ChAT promoter compared with the CAG promoter. The AAV-ChAT transgene expression cassette should be a useful tool for the study of cholinergic neurons in mice, and the broader transduction area of AAV-S warrants further evaluation of this capsid.

Tebentafusp-tebn: A Novel Bispecific T-Cell Engager for Metastatic Uveal Melanoma.

Uveal melanoma is the most common intraocular cancer in adults. Metastatic uveal melanoma has a poor prognosis. Tebentafusp-tebn is the first drug in the new immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC) class of T cell-directed therapy. Tebentafusp-tebn has been shown in a randomized phase III clinical trial to lead to improved overall survival and progression-free survival when compared with single-agent pembrolizumab, ipilimumab, or dacarbazine in previously untreated human leukocyte antigen (HLA)-A*02:01-positive metastatic uveal melanoma patients. Tebentafusp-tebn is now approved by the US Food and Drug Administration in HLA-A*02:01-positive uveal melanoma patients as first-line therapy in the metastatic setting.

Dental services use before and after inpatient admission among privately insured adults in the United States.

BACKGROUND: Oral health has been connected to worse outcomes among hospitalized patients, but access to oral health care services in the hospital setting is limited. It is unknown how a hospital admission affects subsequent dental services use. METHODS: The authors conducted a retrospective analysis of insurance claims data from a national private insurer. Patients were included if they were admitted to the hospital and had visited a dentist at least once in the year before or after admission. Total number of dental visits, as well as Code on Dental Procedures and Nomenclature codes associated with these visits in the year before and after a hospital stay, patient demographic characteristics, hospital admission diagnosis, and length of stay were recorded. Differences in dental services use before and after the hospital stay were calculated. RESULTS: In total, 107,116 patients met inclusion criteria. There were fewer dental visits after admission (mean [standard deviation {SD}] 1.6 [1.7] than before admission (mean [SD] 1.9 [1.8]; P < .0001). Fewer procedures were recorded in the year after discharge (mean [SD] 7.0 [11.4] total Code on Dental Procedures and Nomenclature codes versus 8.5 [12.5] in the year before admission; P < .0001). The number of diagnostic and restorative services delivered was higher after admission, and the number of periodontic, endodontic, oral surgery, and prosthodontic services decreased (overall Pearson χ2, P < .0001). CONCLUSIONS: Patients are less likely to visit a dentist after a hospital stay, although impact on oral health is unknown. PRACTICAL IMPLICATIONS: Hospitalization may contribute to already existing oral health disparities. Hospital teams and dentists should work together to enhance access to oral health care after hospital admission.

Comprehensive, School-Based Preventive Dentistry: Program Details and Students' Unmet Dental Needs.

BACKGROUND: In this paper, we describe the design, program details, and baseline demographics and oral health of participants in ForsythKids, a regional, comprehensive, school-based mobile caries prevention program. METHODS: We solicited all Massachusetts elementary schools with greater than 50% of students receiving free or reduced-price meals. Six schools initially elected to participate, ultimately followed by over 50 schools. Interventions were based on systematic reviews and randomized controlled caries prevention trials. Participating students received semiannual dental examinations, followed by comprehensive preventive care. Summary statistics regarding oral health indicators were derived from individual tooth- and surface-level data. RESULTS: Over a 6-year period, data were collected on 6927 children. The number of students per school ranged from 58 to 681. The overall participation rate was 15%, ranging from 10% to 29%. Overall, 57% of the children were younger than 8 years at baseline. Approximately, 54% of children experienced dental decay on any tooth at baseline; 32% had untreated decay on any tooth, 29% had untreated decay on primary teeth, and 10% untreated decay on permanent teeth. CONCLUSIONS: Untreated dental decay was double the national average, even in schools within several blocks of community dental clinics. These data demonstrate the need for caries prevention beyond the traditional dental practice.

Tilted versus axial implant distribution in the posterior edentulous maxilla: A CBCT analysis.

OBJECTIVES: This study aimed to determine whether distally angulating an implant is a successful strategy to avoid the maxillary sinus and the need for bone augmentation, while increasing the anterior-posterior (A-P) implant distribution in the edentulous maxilla. MATERIALS AND METHODS: In 115 patients with edentulous maxillae, virtual implant planning was performed utilizing cone-beam computer tomographs. Axial (8 mm length) and tilted (12 mm length) dental implants with 30-degree and 45-degree angulation were virtually positioned to avoid entering the maxillary sinus, while maximizing A-P distribution. Measurements were made between the tilted and axial implants to assess the change in A-P distribution of implants at the implant and abutment levels. RESULTS: Forty-seven sites (20.4%) were not able to have either treatment modality with insufficient bone for implant placement. Axial implants were placed more distally than 45-degree and 30-degree tilted implants in 24% and 42% of sites, respectively. The average change in A-P spread measured at the implant level, for 30- and 45-degree tilted implants was -0.25 mm (95% CI -0.76, 0.26) and 1.9 mm (95% CI 1.4, 2.3), respectively. When measured from the center of each multi-unit abutment the average increase in A-P distances for tilted implants appears larger in the 30-degree and 45-degree groups by 0.97 mm and 1.74 mm, respectively compared to measurements at the implant level. CONCLUSIONS: Angulating 12 mm implants provides a limited increase in A-P distribution of implants in edentulous rehabilitation in most situations. In certain patients, the use of 8mm axial implants may provide a greater A-P spread.

Longitudinal caries prevalence in a comprehensive, multicomponent, school-based prevention program.

BACKGROUND: Globally, children's caries prevalence exceeds 30% and has not markedly changed in 30 years. School-based caries prevention programs can be an effective method to reduce caries prevalence, obviate traditional barriers to care, and use aerosol-free interventions. The objective of this study was to explore the clinical effectiveness of a comprehensive school-based, aerosol-free, caries prevention program. METHODS: The authors conducted a 6-year prospective open cohort study in 33 US public elementary schools, providing care to 6,927 children in communities with and without water fluoridation. After dental examinations, dental hygienists provided twice-yearly prophylaxis, glass ionomer sealants, glass ionomer interim therapeutic restorations, fluoride varnish, toothbrushes, fluoride toothpaste, oral hygiene instruction, and referral to community dentists as needed. The authors used generalized estimating equations to estimate the change in the prevalence of untreated caries over time. RESULTS: The prevalence of untreated caries decreased by more than 50%: from 39% through 18% in phase 1, and from 28% through 10% in phase 2. The per-visit adjusted odds ratio of untreated caries was 0.79 (95% confidence interval, 0.73 to 0.85). CONCLUSIONS AND PRACTICAL IMPLICATIONS: This school-based comprehensive caries prevention program was associated with substantial reductions in children's untreated caries, supporting the concept of expanding traditional practices to include office- and community-based aerosol-free care.

Risk of non-syndromic orofacial clefts by maternal rural-urban residence and race/ethnicity: A population-based case-control study in Washington State 1989-2014.

BACKGROUND: Orofacial clefts (OFC) have multifactorial aetiology. Established risk factors explain a small proportion of cases. OBJECTIVES: To evaluate OFC risk by maternal rural residence and race/ethnicity, and test whether these associations changed after US-mandated folic acid fortification. METHODS: This population-based case-control study included all non-syndromic OFC cases among Washington State singleton livebirths between 1989-2014 and birth year-matched controls. Data sources included birth certificates and hospital records. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for OFC by maternal rural-urban residence (adjusted for maternal race/ethnicity) and by maternal race/ethnicity. We evaluated additive and multiplicative effect measure modification by time of folic acid fortification (before vs. after). Probabilistic quantitative bias analysis accounted for potential differential case ascertainment for infants born to Black mothers. RESULTS: The overall non-syndromic OFC birth prevalence was 1.0 per 1000 livebirths (n = 2136 cases). Among controls (n = 25 826), 76% of mothers were urban residents and 72% were of White race/ethnicity. OFC risk was slightly higher for infants born to rural than to urban mothers, adjusting for race/ethnicity (OR 1.12, 95% CI 1.01, 1.25). The association was similar before and after US-mandated folic acid fortification. Compared with infants born to White mothers, OFC risk was higher for American Indian mothers (OR 1.73, 95% CI 1.35, 2.23) and lower for Black (OR 0.62, 95% CI 0.48, 0.81), Hispanic (OR 0.75, 95% CI 0.64, 0.87), and Asian/Pacific Islander (API) mothers (OR 0.87, 95% CI 0.74, 1.02). Bias analysis suggests the observed difference for Black mothers may be explained by selection bias. Post-fortification, the association of OFC with maternal API race/ethnicity decreased and with maternal Black race/ethnicity increased relative to maternal White race/ethnicity. CONCLUSIONS: Infants born to rural mothers and to American Indian mothers in Washington State during 1989-2014 were at higher OFC risk before and after US-mandated folic acid fortification.

Prescribing patterns in a US dental school from 2010 to 2017.

OBJECTIVE: Dental education has an essential role in helping combat the opioid and antibiotic resistance crises. This study evaluates the prescribing practices of clinical instructors, advanced graduate residents, and predoctoral students in an academic dental setting. METHODS: A retrospective chart review was conducted of electronic dental records from the years 2010 to 2017. The proportions of prescriptions for each drug group was calculated by prescribers' training level and specialty. Descriptive statistics were calculated for the daily opioid Morphine Milligram Equivalent (MME) dose prescribed across years and provider characteristics. RESULTS: Over the 8 years, 65,160 prescriptions were written for 10,374 patients by 625 prescribers. The most commonly prescribed drugs were for fluoride-based medications (30%) and antibiotics (24%). Periodontists had the greatest absolute number of opioid analgesics prescriptions (n = 2712); oral maxillofacial surgeons (OMFS) prescribed more opioids than other classes of drug (49%) as a proportion of within-specialty prescriptions. Antibiotics were the most common drugs prescribed by endodontists (46%) and second most common drugs prescribed by periodontists (25%), OMFS (28%), and prosthodontists (21%). From 2010 to 2017, the proportion of prescriptions for antibiotics remained unchanged, while that of fluoride-based drugs increased from 2010 to 2014 and plateaued thereafter. The proportion of prescriptions for opioid analgesics decreased from 18% to 7%. The median daily MME dose across year and provider characteristics stayed constant (<50 MME). CONCLUSION: These results demonstrate encouraging prescription trends for opioid and fluoride-based drugs. Due to the high prevalence of antibiotic prescriptions in academic dental settings, stewardship approaches should be emphasized.

Bayesian variable selection for multivariate zero-inflated models: Application to microbiome count data.

Microorganisms play critical roles in human health and disease. They live in diverse communities in which they interact synergistically or antagonistically. Thus for estimating microbial associations with clinical covariates, such as treatment effects, joint (multivariate) statistical models are preferred. Multivariate models allow one to estimate and exploit complex interdependencies among multiple taxa, yielding more powerful tests of exposure or treatment effects than application of taxon-specific univariate analyses. Analysis of microbial count data also requires special attention because data commonly exhibit zero inflation, i.e., more zeros than expected from a standard count distribution. To meet these needs, we developed a Bayesian variable selection model for multivariate count data with excess zeros that incorporates information on the covariance structure of the outcomes (counts for multiple taxa), while estimating associations with the mean levels of these outcomes. Though there has been much work on zero-inflated models for longitudinal data, little attention has been given to high-dimensional multivariate zero-inflated data modeled via a general correlation structure. Through simulation, we compared performance of the proposed method to that of existing univariate approaches, for both the binary ("excess zero") and count parts of the model. When outcomes were correlated the proposed variable selection method maintained type I error while boosting the ability to identify true associations in the binary component of the model. For the count part of the model, in some scenarios the univariate method had higher power than the multivariate approach. This higher power was at a cost of a highly inflated false discovery rate not observed with the proposed multivariate method. We applied the approach to oral microbiome data from the Pediatric HIV/AIDS Cohort Oral Health Study and identified five (of 44) species associated with HIV infection.

Unjamming and collective migration in MCF10A breast cancer cell lines.

Each cell comprising an intact, healthy, confluent epithelial layer ordinarily remains sedentary, firmly adherent to and caged by its neighbors, and thus defines an elemental constituent of a solid-like cellular collective [1,2]. After malignant transformation, however, the cellular collective can become fluid-like and migratory, as evidenced by collective motions that arise in characteristic swirls, strands, ducts, sheets, or clusters [3,4]. To transition from a solid-like to a fluid-like phase and thereafter to migrate collectively, it has been recently argued that cells comprising the disordered but confluent epithelial collective can undergo changes of cell shape so as to overcome geometric constraints attributable to the newly discovered phenomenon of cell jamming and the associated unjamming transition (UJT) [1,2,5-9]. Relevance of the jamming concept to carcinoma cells lines of graded degrees of invasive potential has never been investigated, however. Using classical in vitro cultures of six breast cancer model systems, here we investigate structural and dynamical signatures of cell jamming, and the relationship between them [1,2,10,11]. In order of roughly increasing invasive potential as previously reported, model systems examined included MCF10A, MCF10A.Vector; MCF10A.14-3-3ζ; MCF10.ErbB2, MCF10AT; and MCF10CA1a [12-15]. Migratory speed depended on the particular cell line. Unsurprisingly, for example, the MCF10CA1a cell line exhibited much faster migratory speed relative to the others. But unexpectedly, across different cell lines higher speeds were associated with enhanced size of cooperative cell packs in a manner reminiscent of a peloton [9]. Nevertheless, within each of the cell lines evaluated, cell shape and shape variability from cell-to-cell conformed with predicted structural signatures of cell layer unjamming [1]. Moreover, both structure and migratory dynamics were compatible with previous theoretical descriptions of the cell jamming mechanism [2,10,11,16,17]. As such, these findings demonstrate the richness of the cell jamming mechanism, which is now seen to apply across these cancer cell lines but remains poorly understood.

Surgical Approach and Periprocedural Outcomes by Race and Ethnicity of Children Undergoing Craniosynostosis Surgery.

BACKGROUND: Surgical repair for craniosynostosis varies depending on the infant's age, location of suture fusion, and approach (e.g., open versus endoscopic). Existing data suggest possible racial and ethnic disparities in timely access to surgical care for craniosynostosis that may, in turn, be associated with surgical approach and perioperative outcomes. This study examined racial and ethnic variation in craniosynostosis operations by surgical approach and perioperative outcomes. METHODS: Data were collected by the 2013 to 2015 Pediatric National Surgical Quality Improvement Program. Patients aged younger than 24 months with diagnoses and procedure codes consistent with surgery for craniosynostosis were identified. Periprocedural characteristics and surgical approach (open, endoscopic/minimally invasive, or both) were examined descriptively, overall, and separately by race and ethnicity. RESULTS: The authors identified 1982 admissions. Mean age at surgery was 7.8 ± 4.7 months. Ninety-one percent of procedures were classified as open operations, 5.8 percent were endoscopic, and 3.4 percent were both open and endoscopic. Relative to white/non-Hispanic patients, Hispanic and nonwhite patients underwent surgery at older ages, experienced longer operative and anesthesia times, and were hospitalized longer. Hispanic patients had the highest rates of open operations. CONCLUSIONS: These data suggest that Hispanic and nonwhite patients tend to undergo craniosynostosis repair at older ages and to have lengthier operations than white/non-Hispanic patients. Although we were unable to examine the root cause(s) of these differences, delayed diagnosis is one factor that might result in surgery at an older age and more complex operations requiring open surgery. Prospective studies examining racial/ethnic disparities are needed to inform a comparison of outcomes associated with surgical approach.

Systematic evasion of the restriction-modification barrier in bacteria.

Bacteria that are recalcitrant to genetic manipulation using modern in vitro techniques are termed genetically intractable. Genetic intractability is a fundamental barrier to progress that hinders basic, synthetic, and translational microbiology research and development beyond a few model organisms. The most common underlying causes of genetic intractability are restriction-modification (RM) systems, ubiquitous defense mechanisms against xenogeneic DNA that hinder the use of genetic approaches in the vast majority of bacteria and exhibit strain-level variation. Here, we describe a systematic approach to overcome RM systems. Our approach was inspired by a simple hypothesis: if a synthetic piece of DNA lacks the highly specific target recognition motifs for a host's RM systems, then it is invisible to these systems and will not be degraded during artificial transformation. Accordingly, in this process, we determine the genome and methylome of an individual bacterial strain and use this information to define the bacterium's RM target motifs. We then synonymously eliminate RM targets from the nucleotide sequence of a genetic tool in silico, synthesize an RM-silent "SyngenicDNA" tool, and propagate the tool as minicircle plasmids, termed SyMPL (SyngenicDNA Minicircle Plasmid) tools, before transformation. In a proof-of-principle of our approach, we demonstrate a profound improvement (five orders of magnitude) in the transformation of a clinically relevant USA300 strain of Staphylococcus aureus This stealth-by-engineering SyngenicDNA approach is effective, flexible, and we expect in future applications could enable microbial genetics free of the restraints of restriction-modification barriers.

Geometric constraints during epithelial jamming.

As an injury heals, an embryo develops, or a carcinoma spreads, epithelial cells systematically change their shape. In each of these processes cell shape is studied extensively whereas variability of shape from cell-to-cell is regarded most often as biological noise. But where do cell shape and its variability come from? Here we report that cell shape and shape variability are mutually constrained through a relationship that is purely geometrical. That relationship is shown to govern processes as diverse as maturation of the pseudostratified bronchial epithelial layer cultured from non-asthmatic or asthmatic donors, and formation of the ventral furrow in the Drosophila embryo. Across these and other epithelial systems, shape variability collapses to a family of distributions that is common to all. That distribution, in turn, is accounted for by a mechanistic theory of cell-cell interaction showing that cell shape becomes progressively less elongated and less variable as the layer becomes progressively more jammed. These findings suggest a connection between jamming and geometry that spans living organisms and inert jammed systems, and thus transcends system details. Although molecular events are needed for any complete theory of cell shape and cell packing, observations point to the hypothesis that jamming behavior at larger scales of organization sets overriding geometrical constraints.

Oral microbiota in youth with perinatally acquired HIV infection.

BACKGROUND: Microbially mediated oral diseases can signal underlying HIV/AIDS progression in HIV-infected adults. The role of the oral microbiota in HIV-infected youth is not known. The Adolescent Master Protocol of the Pediatric HIV/AIDS Cohort Study is a longitudinal study of perinatally HIV-infected (PHIV) and HIV-exposed, uninfected (PHEU) youth. We compared oral microbiome levels and associations with caries or periodontitis in 154 PHIV and 100 PHEU youth. RESULTS: Species richness and alpha diversity differed little between PHIV and PHEU youth. Group differences in average counts met the significance threshold for six taxa; two Corynebacterium species were lower in PHIV and met thresholds for noteworthiness. Several known periodontitis-associated organisms (Prevotella nigrescens, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Filifactor alocis) exhibited expected associations with periodontitis in PHEU youth, associations not observed in PHIV youth. In both groups, odds of caries increased with counts of taxa in four genera, Streptococcus, Scardovia, Bifidobacterium, and Lactobacillus. CONCLUSIONS: The microbiomes of PHIV and PHEU youth were similar, although PHIV youth seemed to have fewer "health"-associated taxa such as Corynebacterium species. These results are consistent with the hypothesis that HIV infection, or its treatment, may contribute to oral dysbiosis.

Scardovia wiggsiae and its potential role as a caries pathogen.

BACKGROUND: Streptococcus mutans has been strongly associated with dental caries but caries also occurs in its absence. Association of a new species, Scardovia wiggsiae with childhood caries suggests this could be a new caries pathogen. HIGHLIGHT: S. mutans is considered a caries pathogen based on its association with caries, and on its ability to produce acid, to survive low pH environments, and to induce caries in experimental animals. S. wiggsiae was significantly associated with severe-early childhood caries in the presence and absence of S. mutans. Further S. wiggsiae was elevated in initial carious lesions in adolescents with fixed orthodontic appliances. S. wiggsiae detection was enriched on a low pH agar suggesting acid-tolerance. S. wiggsiae isolates were acid tolerant and produced acid from several sugars at low initial pH values, and were not arginine deiminase positive, characteristics consistent with potential cariogenicity. Cariogenicity of S. wiggsiae was tested in a rat animal model in parallel with S. mutans. While S. wiggsiae by itself showed minimal caries induction, when co-inoculated with S. mutans, there was significant cavity production. CONCLUSION: S. wiggsiae was associated with advanced and initial caries, is acid tolerant and produces acid to low pH at initial neutral and low pH conditions. In combination with S. mutans, S. wiggsiae was detected in caries in an animal model. Together, these data suggest that S. wiggsiae has many of the characteristics consistent with its being a caries-associated species.

Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

Dentists' and dental students' attitudes, knowledge, preparedness, and willingness related to treatment of people living with HIV/AIDS in China.

OBJECTIVES: This study aims to assess the attitudes, knowledge, preparedness, and willingness of dentists and dental students to treat people-living-with-HIV/AIDS (PLWHA) in China, and to determine the factors associated with willingness to treat. METHODS: We surveyed dentists and dental students in hospitals and dental schools in five regions in China with varying PLWHA prevalence. Survey questions covered demographics, as well as four categories regarding treating PLWHA: knowledge (scaled 0-1), attitude (scaled 1-4), preparedness (scaled 1-4), and willingness to treat (scaled 1-4). Composite scores for each category were calculated as weighted means. Confounder-adjusted regression analysis was performed to determine the factor(s) correlated with willingness to treat. RESULTS: We collected 394 (84 percent) and 462 (90 percent) useable surveys from dentists and dental students respectively. Dentists' mean composite scores were 0.63 (poor knowledge), 2.1 (negative attitude), 2.8 (adequate preparedness), and 2.5 (neutral willingness). Students' mean composite scores were 0.64 (poor knowledge), 2.3 (negative attitude), 2.7 (adequate preparedness), and 2.6 (positive willingness). Forty-five percent of dentists and 59 percent of dental students had scores indicating positive willingness to treat. Attitude was the only factor consistently correlated with willingness to treat. Dentists and dental students scored low in all categories except for preparedness. CONCLUSION: It is imperative that knowledge of HIV/AIDS and attitudes toward PLWHA be further improved during dental training to increase the access to and effectiveness of dental care of PLWHA in China and to enhance their quality of life.