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Palliative care clinicians display less burnout than oncology clinicians. Little is known about the impact of providing both oncology care and primary palliative care in the same setting.The aim was to determine whether nurses providing primary palliative care in addition to oncology care would experience less burnout over time than nurses providing oncology care only.The authors performed secondary analysis of the CONNECT study. Three groups of nurses were evaluated: primary palliative care, non-primary palliative care, and standard care. On study enrollment and after one year, nurses completed the Maslach Burnout Inventory. Multivariable regression analyses were performed to test differences in follow-up burnout scores between groups.Overall burnout rates were low at enrollment for all groups. There were no differences in burnout scores at one year between nurses who provided palliative care and nurses in the other two groups.nbsp.

Purpose: Primary Palliative Care (PPC) interventions are needed to address unmet symptom needs within standard oncology care. We designed an oncology nurse-led PPC intervention using shared care planning to facilitate patient engagement. This analysis examines the prevalence and severity of symptoms reported by patients and how symptoms were addressed on shared care plans.Methods: Secondary analysis of a cluster randomized PPC intervention trial. Adult patients with metastatic solid tumors whose oncologist ‘would not be surprised if the patient died within a year’ were included. Twenty-three oncology nurses received PPC training and conducted up to three monthly visits with patients. Symptom prevalence and severity were assessed prior to each visit using the Edmonton Symptom Assessment Scale (ESAS; 9 symptoms ranked 1-10 with scores ≥4 indicating moderate severity). Nurses collaboratively developed treatment strategies with patients, targeting the most bothersome symptoms for improvement.Results: Among 571 nurse-led PPC visits with 235 patients, the most prevalent and severe symptoms were tiredness (reported at 86% of visits; ESAS ≥4 in 55% of visits), low sense of well-being (78%; ESAS ≥4 in 38%), and poor appetite (69%; ESAS ≥4 in 42%). Moderately severe symptoms were addressed on shared care plans ranging from 4% (drowsiness) to 35% (tiredness) of the time. Symptom management plans developed by PPC-trained oncology nurses primarily focused on non-pharmaceutical interventions (70%) compared to pharmaceutical interventions (30%). Conclusion: The symptoms that patients report most frequently and as most severe on shared care plans were addressed less frequently than expected. Further research is needed to understand how primary palliative care interventions can be designed to more effectively target and improve bothersome symptoms for patients with advanced cancer.

Background: There is increasing need for nonspecialty physicians to deliver palliative care (PC) services to meet patient needs, but many physicians feel inadequately prepared. Objective: We aimed to improve the PC skills of resident physicians through a learner-centered, just-in-time coaching intervention. Design: Our quality improvement initiative consisted of two didactics and brief thrice-weekly coaching sessions that focused on real-time PC questions. Upper level internal medicine residents participated during an inpatient hospitalist rotation. Measurements: Residents completed pre/postrotation surveys of their preparedness in discussing PC topics. Electronic medical record data of documentation of goals-of-care (GOC) discussions and Physician Orders for Life-Sustaining Treatment (POLST) completion in at-risk hospitalized patients (age >65 with two or more hospitalizations in the past six months, or age >90) were obtained and compared with before hospitalization. These data were also compared with data from patients on the same resident hospitalist service during the six-month period before the intervention began. Results: During the 14-month intervention period, 42 residents cared for 232 at-risk patients. Among at-risk patients, 12.9% had a documented GOC discussion before hospitalization, which rose to 57.3% before discharge. Among at-risk patients preintervention, these rates were 5.2% and 25.0%, respectively. Residents reported their preparedness increased across many elements of GOC discussions and rated coaching sessions as useful and relevant to their training. Rates of POLST completion did not differ between preintervention and intervention groups. Conclusions: Brief coaching sessions can integrate PC education into a busy clinical service, improve residents' primary PC skills, and improve GOC documentation.

Importance Guidelines recommend early specialty palliative care for all patients with advanced cancer, but most patients lack access to such services. Objective To assess the effect of CONNECT (Care Management by Oncology Nurses to Address Supportive Care Needs), a primary palliative care intervention delivered by oncology nurses, on patient outcomes. Design, setting, and participants This cluster randomized clinical trial of the CONNECT intervention vs standard care was conducted from July 25, 2016, to October 6, 2020. Participants were adult patients with metastatic solid tumors who were undergoing oncological care and for whom an oncologist would agree with the statement "would not be surprised if the patient died in the next year." The trial was conducted at 17 community oncology practices in western Pennsylvania. Data analyses adhered to the intention-to-treat principle. Interventions The CONNECT intervention included 3 monthly visits with an existing infusion room nurse who was trained to address symptoms, provide emotional support, engage in advance care planning, and coordinate care. Main outcomes and measures The primary outcome was quality of life. At baseline and 3 months, participants completed assessments of quality of life (Functional Assessment of Chronic Illness Therapy-Palliative care: score range, 0-184, with higher scores indicating better quality of life), symptom burden (Edmonton Symptom Assessment Scale: score range, 0-90, with higher scores indicating greater symptom burden), and mood symptoms (Hospital Anxiety and Depression Scale [HADS]: score range, 0-21, with higher scores indicating substantial anxiety and depression). Linear mixed-effects models were used to estimate adjusted mean differences in 3-month outcomes. Preplanned, intensity-adjusted analyses were conducted. Results A total of 672 patients were enrolled (mean [SD] age, 69.3 [10.2] years; 360 women [53.6%]). The mean (SD) number of CONNECT visits completed was 2.2 (1.0). At 3 months, no difference in mean (SD) quality-of-life score was found between the CONNECT and standard care groups (130.7 [28.2] vs 134.1 [28.1]; adjusted mean difference, 1.20; 95% CI, -2.75 to 5.15; P = .55). Similarly, there was no difference between groups in 3-month mean (SD) symptom burden (23.2 [16.6] vs 24.0 [16.1]; adjusted mean difference, -2.64; 95% CI, -5.85 to 0.58; P = .11) or mood symptoms (HADS depression subscale score: 5.1 [3.4] vs 4.8 [3.7], adjusted mean difference, -0.08 [95% CI, -0.71 to 0.57], P = .82; HADS anxiety subscale score: 5.7 [3.9] vs 5.4 [4.2], adjusted mean difference, -0.31 [95% CI, -0.96 to 0.33], P = .34). Intensity-adjusted analyses revealed a larger estimated treatment effect for patients who received a full dose (3 visits) of the CONNECT intervention. Conclusions and relevance This cluster randomized clinical trial found that a primary palliative care intervention that was delivered by oncology nurses did not improve patient-reported outcomes at 3 months. Primary palliative care interventions with a higher dose intensity may be beneficial for most patients with advanced cancer who lack access to palliative care specialists. Trial registration ClinicalTrials.gov Identifier: NCT02712229.

BACKGROUND: Polypharmacy may be particularly burdensome near the end of life, as patients “accumulate” medications to treat and prevent multiple diseases. OBJECTIVE: To evaluate associations between polypharmacy, symptom burden, and quality of life (QOL) in patients with advanced, life-limiting illness (clinician-estimated, 1 month–1 year). DESIGN: Secondary analysis of baseline data from a trial of statin discontinuation. PARTICIPANTS: Adults with advanced, life-limiting illness. MAIN MEASURES: Polypharmacy was assessed by summing the number of non-statin medications taken regularly or as needed. Symptom burden was assessed using the Edmonton Symptom Assessment Scale (range 0–90; higher scores indicating greater symptom burden) and QOL was assessed using the McGill QOL Questionnaire (range 0–10; higher scores indicating better QOL). Linear regression models assessed associations between polypharmacy, symptom burden, and QOL. KEY RESULTS: Among 372 participants, 47% were age 75 or older and 35% were enrolled in hospice. The mean symptom score was 27.0 (standard deviation (SD) 16.1) and the mean QOL score was 7.0 (SD 1.3). The average number of non-statin medications was 11.6 (SD 5.0); one-third of participants took ≥ 14 medications. In adjusted models, higher polypharmacy was associated with higher symptom burden (coefficient 0.81; p

Objective: Develop and pilot-test a nurse-led primary palliative care intervention for patients with advanced hematologic malignancies. Background: Nurse-led primary palliative care interventions may improve outpatient palliative care provision for patients with advanced hematologic malignancies. Methods: This two-phase, single-arm pilot study involved patients with recurrent or resistant hematologic malignancies, their caregivers, and oncology clinicians at two US-based urban, university-affiliated oncology clinics. Measurements included feasibility (enrollment rates, intervention fidelity, and outcome assessment rates) and acceptability (patient, caregiver, and clinician surveys). Results: In Phase 1 we developed and implemented an oncology nurse-led primary palliative care intervention for patients with recurrent or resistant hematologic malignancies and their caregivers. In Phase 2, we tested feasibility and acceptability. Twenty-six patient participants enrolled. Consent-to-approach rate was 78% and enrolled-to-consent rate was 84%. All enrolled participants received the intervention per protocol. Sixty-nine percent of patients and 100% of caregivers reported that the intervention helped them better understand the patient's illness and cope. Seventy-five percent of oncologists reported that the intervention improved their patients' quality of care, and 25% reported that it helped them take better care of patients. Conclusions: Although our pilot of oncology nurse-led primary palliative care for patients with advanced hematologic malignancies met some of its secondary feasibility endpoints, it did not meet its primary feasibility endpoint (enrollment) and acceptability was mixed. Protecting nursing staff time, increasing patient and clinician involvement in intervention development, and identifying patients with highest supportive needs may improve feasibility and acceptability of future primary palliative care in hematologic malignancy trials.

Background Failure to deliver care near the end of life that reflects the needs, values and preferences of patients with advanced cancer remains a major shortcoming of our cancer care delivery system. Methods A mixed-methods comparative effectiveness trial of in-person advance care planning (ACP) discussions versus web-based ACP is currently underway at oncology practices in Western Pennsylvania. Patients with advanced cancer and their caregivers are invited to enroll. Participants are randomized to either (1) in-person ACP discussions via face-to-face visits with a nurse facilitator following the Respecting Choices® Conversation Guide or (2) web-based ACP using the PREPARE for your care™ web-based ACP tool. The trial compares the effect of these two interventions on patient and family caregiver outcomes (engagement in ACP, primary outcome; ACP discussions; advance directive (AD) completion; quality of end-of-life (EOL) care; EOL goal attainment; caregiver psychological symptoms; healthcare utilization at EOL) and assesses implementation costs. Factors influencing ACP effectiveness are assessed via in-depth interviews with patients, caregivers and clinicians. Discussion This trial will provide new and much-needed empirical evidence about two patient-facing ACP approaches that successfully overcome limitations of traditional written advance directives but entail very different investments of time and resources. It is innovative in using mixed methods to evaluate not only the comparative effectiveness of these approaches, but also the contexts and mechanisms influencing effectiveness. Data from this study will inform clinicians, payers and health systems seeking to adopt and scale the most effective and efficient ACP strategy in real-world oncology settings.

Although children with oral clefts have a higher risk for dental anomalies when compared with the general population, prior studies have shown conflicting results regarding their dental decay risk. Also, few studies have assessed dental decay risk in unaffected relatives of children with clefts. Thus, the question of increased risk of dental decay in individuals with oral clefts or their unaffected relatives is still open for empirical investigation. This study characterizes dental decay in the largest international cohort to date of children with nonsyndromic clefts and their relatives, as compared with controls, and it addresses whether families with oral clefts have a significantly increased risk for dental decay versus the general population. A total of 3,326 subjects were included: 639 case probands, 1,549 unaffected relatives, and 1,138 controls. Decay was identified from in-person dental examinations or intraoral photographs. Case-control differences were tested with regression analysis. No significant differences were shown in percentage decayed and filled teeth and decayed teeth in the primary dentition (dft, dt) and permanent dentition (DFT, DT) in cases versus controls. In the cleft region, no significant differences were seen in primary or permanent decay (dt, DT) when compared with controls. No difference was found with regard to cleft type and percentage dft, dt, DFT, and DT in case probands. Nonsignificant differences were found in unaffected siblings and parents versus controls (primary and permanent dentitions). Collectively, these findings indicate that individuals with nonsyndromic oral clefts and their families do not have a higher dental decay risk as compared with the general population. These results suggest that either genetic or environmental factors underlying a higher susceptibility for dental anomalies do not increase caries risk or that the seemingly higher risk for dental decay associated with increased dental anomalies in case probands may be superseded by possible greater access to dental care.

Children with oral clefts show a wide range of dental anomalies, adding complexity to understanding the phenotypic spectrum of orofacial clefting. The evidence is mixed, however, on whether the prevalence of dental anomalies is elevated in unaffected relatives and is mostly based on small samples. In the largest international cohort to date of children with nonsyndromic clefts, their relatives, and controls, this study characterizes the spectrum of cleft-related dental anomalies and evaluates whether families with clefting have a significantly higher risk for such anomalies compared with the general population. A total of 3,811 individuals were included: 660 cases with clefts, 1,922 unaffected relatives, and 1,229 controls. Dental anomalies were identified from in-person dental exams or intraoral photographs, and case-control differences were tested using χ2 statistics. Cases had higher rates of dental anomalies in the maxillary arch than did controls for primary (21% vs. 4%, P = 3 × 10−8) and permanent dentitions (51% vs. 8%, P = 4 × 10−62) but not in the mandible. Dental anomalies were more prevalent in cleft lip with cleft palate than other cleft types. More anomalies were seen in the ipsilateral side of the cleft. Agenesis and tooth displacements were the most common dental anomalies found in case probands for primary and permanent dentitions. Compared with controls, unaffected siblings (10% vs. 2%, P = 0.003) and parents (13% vs. 7%, P = 0.001) showed a trend for increased anomalies of the maxillary permanent dentition. Yet, these differences were nonsignificant after multiple-testing correction, suggesting genetic heterogeneity in some families carrying susceptibility to both overt clefts and dental anomalies. Collectively, the findings suggest that most affected families do not have higher genetic risk for dental anomalies than the general population and that the higher prevalence of anomalies in cases is primarily a physical consequence of the cleft and surgical interventions.

Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1–5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries. Fil: Shimizu, T.. Nihon University of Dentistry; Japón Fil: Deeley, K.. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, J.. University of Pittsburgh; Estados Unidos Fil: Faraco Junior, I. M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Brancher, J. A.. Pontifical Catholic University of Paraná; Brasil Fil: Pecharki, G. D.. Pontifical Catholic University of Paraná; Brasil Fil: Küchler, E. C.. Universidade Federal Fluminense; Brasil Fil: Tannure, P. N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, A.. Universidade Federal do Rio de Janeiro; Brasil Fil: Vieira, T. C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, A.. Istanbul Medipol Universit; Turquía Fil: Yildirim, M.. Istanbul University; Turquía Fil: Mereb, J. C.. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Resick, J. M.. University of Pittsburgh; Estados Unidos Fil: Brandon, C. A.. University of Pittsburgh; Estados Unidos Fil: Cooper, M. E.. University of Pittsburgh; Estados Unidos Fil: Seymen, F.. Istanbul University; Turquía Fil: Costa, M. C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, J. M.. Universidade Federal Fluminense; Brasil Fil: Trevilatto, P. C.. Pontifical Catholic University of Paraná; Brasil Fil: Orioli, I. M.. Universidade Federal do Rio de Janeiro; Brasil. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Castilla, Eduardo Enrique. Instituto Oswaldo Cruz; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Marazita, M. L.. University of Pittsburgh; Estados Unidos Fil: Vieira, A. R.. University of Pittsburgh; Estados Unidos

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.

Caries is a multifactorial disease, and studies aiming to unravel the factors modulating its etiology must consider all known predisposing factors. One major factor is bacterial colonization, and Streptococcus mutans is the main microorganism associated with the initiation of the disease. In our studies, we have access to DNA samples extracted from human saliva and blood. In this report, we tested a real-time PCR assay developed to detect copies of genomic DNA from Streptococcus mutans in 1,424 DNA samples from humans. Our results suggest that we can determine the presence of genomic DNA copies of Streptococcus mutans in both DNA samples from caries-free and caries-affected individuals. However, we were not able to detect the presence of genomic DNA copies of Streptococcus mutans in any DNA samples extracted from peripheral blood, which suggests the assay may not be sensitive enough for this goal. Values of the threshold cycle of the real-time PCR reaction correlate with higher levels of caries experience in children, but this correlation could not be detected for adults. Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen B.. University of Pittsburgh; Estados Unidos Fil: Callahan, Nicholas F.. University of Pittsburgh; Estados Unidos Fil: Noel, Jacqueline B.. University of Pittsburgh; Estados Unidos Fil: Anjomshoaa, Ida. University of Pittsburgh; Estados Unidos Fil: Carricato, Wendy M.. University of Pittsburgh; Estados Unidos Fil: Schulhof, Louise P.. University of Pittsburgh; Estados Unidos Fil: DeSensi, Rebecca S.. University of Pittsburgh; Estados Unidos Fil: Gandhi, Pooja. University of Pittsburgh; Estados Unidos Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Rozhon, Christopher. University of Pittsburgh; Estados Unidos Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Yildirim, Mine. Istanbul University; Turquía Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Mereb, Juan C.. Hospital de Area El Bolsón; Argentina Fil: Letra, Ariadne. University of Pittsburgh; Estados Unidos Fil: Menezes, Renato. University of Pittsburgh; Estados Unidos Fil: Wendell, Steven. University of Pittsburgh; Estados Unidos Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Orioli, Ieda Maria. Hospital de Area El Bolsón; Argentina Fil: Seymen, Figen. Istanbul Universit; Turquía Fil: Weyant, Robert J.. University of Pittsburgh; Estados Unidos Fil: Crout, Richard. West Virginia University; Estados Unidos Fil: McNeil, Daniel W.. West Virginia University; Estados Unidos Fil: Modesto, Adriana. University of Pittsburgh; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos

Aims, background and objectives: A growing body of research demonstrates that teaching close-reading and reflective writing to clinicians improves their ability to provide patient- and person-centered care. Through narrative medicine workshops, providers gain skills that can improve relationships with patients, increase empathy among clinicians and enhance clinical care. The goal of the event series (book discussion and reflective writing sessions) offered at the University of Pittsburgh School of Dental Medicine, USA was to provide participants an interactive opportunity to practise and reflect upon the basic tenets of narrative medicine. Methods: The objectives were to recognize how a written text can inform and enhance empathetic and humanistic thinking and to develop an increased appreciation for the importance of humanistic thinking in healthcare. The goal of this article was to share the outcomes of a unique program, which was offered in an interprofessional setting and organized by collaborators across disciplines within and outside of the healthcare professions. To evaluate the overall effectiveness of the introductory presentation, book discussion and reflective writing sessions, anonymous surveys were employed to study participants’ perception about the role of literature in healthcare, the role of reflection in the provision of care and insights gained in the sessions. Results: The study revealed overwhelmingly positive responses by the participants to the programming. Qualitative data analysis revealed multiple areas of learning. Discussion and Conclusion: Due to the success of the workshop series, the School of Dental Medicine will offer the event again and expects it to become a sustained yearly event that fosters collaborations across different schools of the University.

Nonsyndromic cleft lip ± cleft palate is a complex disease with a wide phenotypic spectrum; occult defects of the superior orbicularis oris muscle may represent the mildest subclinical form of the lip portion of the phenotype. This study used high-resolution ultrasonography to compare the frequency of discontinuities in the OO muscle in 525 unaffected relatives of individuals with nonsyndromic cleft lip ± cleft palate versus 257 unaffected controls. OO muscle discontinuities were observed in 54 (10.3%) of the non-cleft relatives, compared to 15 (5.8%) of the controls—a statistically significant increase (P = 0.04). Male relatives had a significantly higher rate of discontinuities than male controls (12.0% vs. 3.2%; P = 0.01); female relatives also had a higher rate of discontinuities than female controls, but the increase was not statistically significant (8.9% vs. 7.4%; P = 0.56). These data confirm the hypothesis that subepithelial OO muscle defects are a mild manifestation of the cleft lip phenotype. Identification of subepithelial OO muscle defects may be important in a clinical setting, as a means of providing more accurate recurrence risk estimates to relatives in cleft families. Furthermore, the expansion of the cleft lip ± cleft palate phenotypic spectrum should improve the power of genetic studies. © 2007 Wiley-Liss, Inc.

Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher’s exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries. Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Shimizu, Takehiko. Nihon University of Dentistry at Matsudo; Japón Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Dizak, Piper M.. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy D. University of Pittsburgh; Estados Unidos Fil: Faraco Jr., Italo M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Brancher, Joao A.. Universidade Federal do Paraná; Brasil Fil: Pecharki, Giovana D.. Universidade Federal do Paraná; Brasil Fil: Kuchler, Erika C. University of Pittsburgh; Estados Unidos Fil: Tannure, Patricia N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, Andrea. Universidade Federal Fluminense; Brasil Fil: Vieira, Thays C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Mereb, J. C.. Estudio Colaborativo Latino Americano de Malformaciones Congénita; Argentina Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Letra, Ariadme. University of Texas Health Science Center at Houston; Estados Unidos Fil: Silva, Renato M.. University of Texas Health Science Center at Houston; Estados Unidos Fil: Cooper, Margaret E.. University of Pittsburgh; Estados Unidos Fil: Seymen, Figen. Istanbul University; Turquía Fil: Costa, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, Jose M. Universidade Federal Fluminense; Brasil Fil: Trevilatto, Paula C.. Universidade Federal do Paraná; Brasil Fil: Orioli, Eeda M.. Instituto Nacional de Metrologia, Qualidade e Tecnologia; Brasil Fil: Castilla, Eduardo Enrique. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

The identification of individuals at a higher risk of developing caries is of great interest. Isolated forms of cleft lip and palate are among the most common craniofacial congenital anomalies in humans. Historically, several reports suggest that individuals born with clefts have a higher risk for caries. Caries continues to be the most common infectious noncontagious disease worldwide and a great burden to any health system. The identification of individuals of higher susceptibility to caries is of great interest. In this paper, we assessed caries experience of 1,593 individuals from three distinct populations. The study included individuals born with clefts, their unaffected relatives, and unrelated unaffected controls that were recruited from areas with similar cultural pressures and limited access to dental care. DMFT/dmft scores were obtained, and caries experience rates were compared among the three groups in each geographic area. Individuals born with clefts did not present higher caries experience in comparison to their unaffected relatives or unrelated unaffected controls. Women tend to present higher caries rates in comparison to men. Our work provides strong evidence that individuals born with clefts are not at higher risk to caries; however, women tend to have more severe caries experience., Instituto Multidisciplinario de Biología Celular

WOS: 000309554700021 PubMed ID: 23028741 There is evidence for a genetic component in caries susceptibility, and studies in humans have suggested that variation in enamel formation genes may contribute to caries. For the present study, we used DNA samples collected from 1,831 individuals from various population data sets. Single nucleotide polymorphism markers were genotyped in selected genes (ameloblastin, amelogenin, enamelin, tuftelin, and tuftelin interacting protein 11) that influence enamel formation. Allele and genotype frequencies were compared between groups with distinct caries experience. Associations with caries experience can be detected but they are not necessarily replicated in all population groups and the most expressive results was for a marker in AMELX (p = 0.0007). To help interpret these results, we evaluated if enamel microhardness changes under simulated cariogenic challenges are associated with genetic variations in these same genes. After creating an artificial caries lesion, associations could be seen between genetic variation in TUFT1 (p = 0.006) and TUIP11 (p = 0.0006) with enamel microhardness. Our results suggest that the influence of genetic variation of enamel formation genes may influence the dynamic interactions between the enamel surface and the oral cavity. National Institutes of Health [R01-DE018914, R01-DE016148] This research is supported by National Institutes of Health grants R01-DE018914 and R01-DE016148. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.