High speed of fork progression induces DNA replication stress and genomic instability.

Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle1. Replication stress induces fork stalling and fuels genome instability2. The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer2. Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse3. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl)ation (PARylation) and the PCNA interactor p21Cip1 (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in)stability and rational cancer treatment.

Is Group B Streptococcus Colonization Associated with Maternal Peripartum Infection in an Era of Routine Prophylaxis?

OBJECTIVE: This study aimed to assess whether colonization with group B streptococcus (GBS) is associated with maternal peripartum infection in an era of routine prophylaxis. STUDY DESIGN: This study presented a secondary analysis of women delivering ≥37 weeks who underwent a trial of labor from the U.S. Consortium on Safe Labor (CSL) study. The exposure was maternal GBS colonization and the outcome was a diagnosis of chorioamnionitis, and secondarily, analyses were restricted to deliveries not admitted in labor and measures of postpartum infection (postpartum fever, endometritis, and surgical site infection). Logistic regression with generalized estimating equations was used accounting for within-woman correlations. Models adjusted for maternal age, parity, race, prepregnancy body mass index, pregestational diabetes, insurance status, study site/region, year of delivery, number of vaginal exams from admission to delivery, and time (in hours) from admission to delivery. RESULTS: Among 170,804 assessed women, 33,877 (19.8%) were colonized with GBS and 5,172 (3.0%) were diagnosed with chorioamnionitis. While the frequency of GBS colonization did not vary by chorioamnionitis status (3.0% in both groups), in multivariable analyses, GBS colonization was associated with slightly lower odds of chorioamnionitis (adjusted odds ratio [AOR]: 0.89; 95% confidence interval [CI]: 0.83-0.96). In secondary analyses, this association held regardless of spontaneous labor on admission; and the odds of postpartum infectious outcomes were not higher with GBS colonization. CONCLUSION: In contrast to historical data, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis. KEY POINTS: · Data in an era prior to routine group B streptococcus (GBS) screening and prophylaxis showed that maternal GBS colonization was associated with a higher frequency of maternal peripartum infection.. · In the current study, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis.. · The results highlight potential benefits of GBS screening and intrapartum antibiotic prophylaxis beyond neonatal disease prevention, including mitigating the risk of maternal infectious morbidity..

The effect of orthognathic surgery on facial recognition algorithm analysis.

INTRODUCTION: The purpose of this study was to evaluate the ability of a publicly available facial recognition application program interface to calculate similarity scores for presurgical and postsurgical photographs of patients who underwent orthognathic surgeries. Our primary objective was to identify which surgical procedure(s) had the greatest effect(s) on the similarity score. METHODS: Existing photographs for 25 orthodontic-orthognathic patients were analyzed using the application program interface to calculate similarity scores between the presurgical and postsurgical photographs. Photographs from 2 presurgical timepoints were compared as controls. Both relaxed and smiling photographs were included to assess the added impact of a facial pose. Patient characteristics and surgery types were recorded for statistical analysis. Nonparametric Kruskal-Wallis rank-sum tests were performed to analyze the relationship between patient characteristics and similarity scores. Multiple comparisons Wilcoxon rank-sum tests were performed on the statistically significant characteristics. RESULTS: Recognition scores were significantly lower after orthognathic surgery at rest (P = 0.009) and smiling (P <0.001). Patients receiving both LeFort I and bilateral sagittal split osteotomy (BSSO) surgeries had a lower median similarity score compared with those that received only BSSO (P = 0.009) when comparing relaxed photographs before and after surgery. Similarly, for the score comparing presurgical relaxed photographs to postsurgical smiling photographs, patients that received both surgeries were found to have lower similarity scores compared with those receiving only BSSO (P = 0.036). CONCLUSIONS: Two-jaw surgeries were associated with a statistically significant decrease in similarity score when compared with 1-jaw procedure. Pose was also found to be a factor influencing similarity scores, especially when comparing presurgical relaxed photographs to postsurgical smiling photographs.

A needle in a haystack: Report of a retained archwire fragment in the pterygomandibular space.

This clinical report describes a retained archwire fragment, discovered during a new-patient examination of a young woman seeking orthodontic retreatment. The diagnostic process, care coordination, and patient management decisions are discussed, along with a brief exploration of clinical considerations associated with this incident. A suggested emergency prevention and response protocol is also presented.

Postural Preference and Musculoskeletal Complaints in Oral and Maxillofacial Surgeons.

PURPOSE: Oral and maxillofacial surgeons traditionally have musculoskeletal pain. The aim of this study was to determine the postural preferences of oral and maxillofacial surgeons and their effect on musculoskeletal pain. MATERIALS AND METHODS: The authors designed and implemented a cross-sectional study. The association of demographic characteristics with postural preferences and use of loupes was explored. Then, the relation of demographic characteristics, postural preferences, and use of loupes to painful musculoskeletal complaints was analyzed. Contingency analysis was used to compare participants' responses and multiple logistic regression analysis was used to identify relevant predictor variables. RESULTS: The sample was composed of 153 oral and maxillofacial surgeons, of which 32% indicated that they had pain attributable to their practice that lasted longer than 2 weeks. Practitioners reported neck and back pain as being most common. Eighty-four percent of practitioners stood for extractions and placement of implants. Those who stood did so for visibility. Practitioners who sat indicated they did so for orthopedic reasons (P < .001). Thirty-one percent of practitioners indicated loupes use. Those who used loupes were more likely to report pain (P = .022). CONCLUSION: Most respondents stood and did not use loupes. Those who did use loupes were more likely to report pain. Those who stood did so for visibility; those who sat did so for orthopedic reasons. Almost one third of respondents reported pain lasting at least 2 weeks during practice.

Telemedicine Consultations in Oral and Maxillofacial Surgery: A Follow-Up Study.

PURPOSE: The purpose of this study was to follow up on the previous study in evaluating the efficiency and reliability of telemedicine consultations for preoperative assessment of patients. MATERIALS AND METHODS: A retrospective study of 335 patients over a 6-year period was performed to evaluate success rates of telemedicine consultations in adequately assessing patients for surgical treatment under anesthesia. Success or failure of the telemedicine consultation was measured by the ability to triage patients appropriately for the hospital operating room versus the clinic, to provide an accurate diagnosis and treatment plan, and to provide a sufficient medical and physical assessment for planned anesthesia. Data gathered from the average distance traveled and data from a previous telemedicine study performed by the National Institute of Justice were used to estimate the cost savings of using telemedicine consultations over the 6-year period. RESULTS: Practitioners performing the consultation were successful 92.2% of the time in using the data collected to make a diagnosis and treatment plan. Patients were triaged correctly 99.6% of the time for the clinic or hospital operating room. Most patients (98.0%) were given sufficient medical and physical assessment and were able to undergo surgery with anesthesia as planned at the clinic appointment immediately after telemedicine consultation. Most patients (95.9%) were given an accurate diagnosis and treatment plan. The estimated amount saved by providing consultation by telemedicine and eliminating in-office consultation was substantial at $134,640. CONCLUSION: This study confirms the findings from previous studies that telemedicine consultations are as reliable as those performed by traditional methods.

The Use of Telemedicine in Oral and Maxillofacial Surgery.

PURPOSE: To determine the perceived utility and demand for the application of telemedicine for improved patient care between nonsurgical dental practitioners (GPs) and oral and maxillofacial surgeons (OMS). MATERIALS AND METHODS: Two distinct questionnaires were made, one for GPs and one for OMSs. The GP questionnaire was sent to practicing Virginia Dental Association members on an e-mail list (approximately 2,200). The OMS questionnaire was sent by the Virginia Society of Oral Maxillofacial Surgery to members on an e-mail list (approximately 213). Questionnaires included questions about access to care, benefits of telemedicine consultations, reliability of telemedicine consultations, and perceived barriers against and opportunities for the implementation of telemedicine. The questionnaire was completed by 226 GP and 41 OMS respondents. RESULTS: There was a significant difference among responses of GPs based on practice location: rural patients had a longer average time from referral to OMS consultation (P = .003), rural patients traveled longer distances (P < .0001), rural practitioners referred more patients (P = .0038), and rural GPs referred more single-tooth implant cases (P = .0039). GP respondents moderately agreed to statements about the benefits of telemedicine, whereas OMS respondents were more neutral. GPs responded they would refer more patients (4.4) if consultations could be performed by telemedicine. OMSs agreed that more referrals would influence their decision to provide telemedicine consultations (51%). Practitioners had neutral perceptions about the reliability of telemedicine. OMS respondents agreed they would implement telemedicine in their practice if it provided equally good consultations as in-office visits. CONCLUSION: According to the present findings, telemedicine could be an important step in the right direction for overcoming current issues with patient access to care and increasing health care costs. The benefits of telemedicine technology have been documented and will continue to be seen with wider application of its use in other areas of health care such as oral and maxillofacial surgery.

Predicting neonatal respiratory morbidity by lamellar body count and gestational age.

AIMS: To develop a predictive model for assessing the risk of developing neonatal respiratory morbidity using lamellar body counts (LBCs) and gestational age (GA) to provide a more patient-specific assessment. METHODS: Retrospective cohort study of patients' ≥32 weeks' gestation who received amniocentesis with LBC analysis over a 9-year period. Respiratory morbidity was defined as respiratory distress syndrome, transient tachypnea of the newborn or oxygen requirement for >24 h. Logistic regression analyses were used to predict the absolute risk and odds of respiratory morbidity as a function of GA and lamellar body count. RESULTS: Two hundred and sixty-seven mother-infant pairs included in the analysis with 32 cases (12.0%) of respiratory morbidity. When compared to those without respiratory morbidity, neonates with respiratory morbidity had amniocentesis performed at an earlier median GA, had lower mean birthweight and had lower median LBC (P<0.01). The GA specific absolute risks and odds ratios for the presence of respiratory morbidity were calculated. The predicted absolute risks of neonatal respiratory morbidity ranged from 38% at 32 weeks to 6% at 40 weeks when LBC were 35,000/µL. CONCLUSION: GA specific predicted risk of neonatal respiratory morbidity using LBC provides a statistical model, which can aid clinicians in individually counseling patients regarding the absolute risk of their neonate developing respiratory morbidity.

Management of Pregnancy and Survival of Infants with Trisomy 13 or Trisomy 18.

Objective The objective of this study was to describe antenatal/intrapartum management and survival of liveborn infants with known trisomy 13 (T13) or trisomy 18 (T18) based on planned neonatal care. Study Design This is a retrospective cohort study of singleton pregnancies complicated by T13/T18 at a tertiary center from 2004 to 2015. We included pregnancies with antenatal or neonatal cytogenetic T13/T18 diagnosis and excluded those which were terminated or had a fetal demise < 20 weeks. We compared antenatal/intrapartum management and neonatal survival by planned neonatal care, defined as either neonatal intervention (INT), including neonatal cardiopulmonary resuscitative measures or comfort care (CC) without resuscitative measures. Results In this study, 32 women (10 with T13 and 22 with T18) met study criteria; 12 (38%) elected INT and 20 (62%) CC. Compared with those who elected INT, women who elected CC were more likely to undergo elective induction (40 vs. 0%, p = 0.01), have an intrapartum stillbirth (0 vs. 32%, p = 0.14), and deliver vaginally (25 vs. 63%, p < 0.01). In neonatal survival analysis (n = 26), median survival was longer in the INT group compared with CC group (64 days [interquartile range, IQR: 2, 155) vs. 3 days [IQR]: 0.3, 42), p = 0.28), but survival to hospital discharge was similar (53 vs. 57%, p = 0.95). Conclusion Regardless of desired level of neonatal INT, many women who continue pregnancies complicated by T13/18 have infants who survive beyond hospital discharge.

Risk of uterine rupture among women attempting vaginal birth after cesarean with an unknown uterine scar.

OBJECTIVE: The purpose of this study was to estimate the association of uterine rupture and previous incision type, either unknown or low transverse, among women who attempt a trial of labor after 1 previous cesarean delivery. STUDY DESIGN: We conducted a secondary analysis of a prospective multicenter observational study of 15,519 women with term singletons who attempted a trial of labor after 1 previous cesarean delivery. Odds ratios for the association between uterine incision location, either unknown or low transverse, and uterine rupture were estimated with the use of multivariable logistic regression. RESULTS: Between 1999 and 2002, 99 of the 15,519 women (0.64%) who attempted a trial of labor after 1 previous cesarean delivery experienced a uterine rupture. Pregnant women with an unknown scar had lower odds of uterine rupture (adjusted odds ratio, 0.71; 95% confidence interval, 0.37-1.37) compared with women with a known low transverse scar. Other adverse maternal outcomes did not differ between the 2 groups of women. CONCLUSION: Among this cohort, women with an unknown uterine incision who attempted a trial of labor were not at increased risk of uterine rupture compared with women with a known low transverse incision.

Periosteal osteosarcoma of the mandible: a case report.

This report describes a rare case of a periosteal osteosarcoma of the mandible in a 50-year-old African-American woman who showed no underlying bony changes at panoramic radiography or computed tomography. This report describes the diagnostic workup used to obtain the definitive diagnosis and the surgical treatment and recommended method for subsequent tumor surveillance. Emphasis is placed on distinguishing periosteal osteosarcomas as a separate entity from conventional intraosseous osteosarcomas in the head and neck region.

Nonreassuring fetal status during trial of labor after cesarean.

OBJECTIVE: Concern for uterine rupture has led to the decline in vaginal births after cesarean. Nonreassuring fetal status (NRFS) may precede uterine rupture. The objective of this study was to estimate the risks of uterine rupture, uterine dehiscence, and adverse fetal outcomes associated with NRFS during trial of labor after cesarean (TOLAC). STUDY DESIGN: In a retrospective cohort study of the previously reported Maternal-Fetal Medicine Units Network prospective cohort cesarean registry, we compared women undergoing repeat cesarean for NRFS after TOLAC to those requiring repeat cesarean for other intrapartum indications. Exclusion criteria included women with a prior cesarean who underwent elective or indicated repeat cesarean or women with a multiple gestation. Primary outcomes included uterine rupture or dehiscence. Secondary outcomes included 5-minute Apgar score <7 and neonatal intensive care unit admission. Planned subanalyses for term and preterm deliveries were performed. Stratified and logistic regression analyses were used. RESULTS: Of 17,740 women undergoing TOLAC, 4754 (26.8%) had a failed vaginal birth after cesarean. Of those, NRFS was the primary indication for cesarean in 1516 (31.9%). Women with NRFS as the primary indication for repeat cesarean were at increased risk of uterine rupture (adjusted odds ratio, 3.32; 95% confidence interval, 2.21-5.00), uterine dehiscence (adjusted odds ratio, 1.70; 95% confidence interval, 1.09-2.65), 5-minute Apgar score <7, and neonatal intensive care unit admission compared to women with other primary indications. CONCLUSION: Women attempting TOLAC who require repeat cesarean for NRFS are at increased risk of uterine rupture and uterine dehiscence.

Regulation of stem cell plasticity: mechanisms and relevance to tissue biology and cancer.

Embryonic stem cells (ESCs) are associated with a high degree of plasticity, which allows them to self-renew and differentiate into every somatic cell. During differentiation, ESCs follow a hierarchically organized pattern towards tissue specificity, which ultimately results in permanent cell cycle arrest and a loss of cellular plasticity. In contrast to their normal somatic counterparts, cancer cells retain elevated levels of plasticity that include switches between epithelial and mesenchymal phenotypes. Transitions between these cell stages have lately been linked to the reacquisition of stem cell features during cellular reprogramming and dedifferentiation in normal and neoplastic cells. In this review, we discuss the key factors and their interplay that is needed to regain a stem cell stage with a particular emphasis put on the impact of cell cycle regulation. Apart from mechanistic insights into the emerging fundamental processes of stem cell plasticity and capacity to transdifferentiate, we also highlight implications of these concepts for tissue biology, tumorigenesis, and cancer therapy.

Accuracy of predicting the duration of a surgical operation.

PURPOSE: The ability to predict how long a particular operation will take is important for maintaining operating room efficiency. The purpose of this study was to determine how accurate oral and maxillofacial surgeons (OMSs) can be in making this determination. MATERIALS AND METHODS: Three experienced OMSs predicted their operating times for various operations; these predictions were compared with the actual times. The cases were then grouped into those with accurate predictions and those with overestimated and underestimated times, and the operative reports were reviewed for possible operation trends or other contributing factors. RESULTS: In the 100 cases analyzed, the surgeons correctly estimated operating times 26% of the time, overestimated 42% of the time, and underestimated 32% of the time. In the 42 overestimated times, 10 cases involved multiple tooth extractions or removal of impacted third molars, and 8 cases involved orthognathic surgery. In the 32 underestimated cases, 7 involved orthognathic surgery and 8 involved the open reduction of fractures. The 26 accurately estimated cases involved 7 cases of multiple tooth extractions or impacted third molar removal and 5 cases of arthroscopic temporomandibular joint lysis and lavage. CONCLUSIONS: Although operating times need to be used for scheduling purposes, they can be highly unpredictable. Surgeons need to constantly analyze their predictions for confounding factors in order to improve their accuracy.

Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial.

OBJECTIVE: To compare the safety and tolerability of metformin to insulin for glycemic control among women with preexisting type 2 and early A2 gestational diabetes. STUDY DESIGN: Women with preexisting type 2 diabetes and those diagnosed with gestational diabetes who required medical management prior to 20 weeks were randomly assigned to metformin or insulin. Glycemic control, defined as >50% capillary blood glucose within target range, was compared between groups. Other outcomes included patient tolerance, neonatal and obstetric complications, maternal weight gain, neonatal cord blood C-peptide, and patient satisfaction with therapy. RESULTS: Twenty-eight women completed the study, with 14 in each group. Of the 15 women assigned to metformin, 100% continued to receive metformin until delivery, although 43% required supplemental insulin to achieve glycemic control. Glucose measures did not differ between the groups, and the proportion who met fasting and postprandial glycemic target values did not differ between the groups. Women treated with metformin had significantly fewer subjective episodes of hypoglycemia compared with those using insulin (0% versus 36%; p = 0.04) as well as reported glucose values < 60 mg/dL (7.1% versus 50%; p = 0.03). CONCLUSION: Metformin should be considered for treatment of overt diabetes and early A2 gestational diabetes in pregnancy.

Robotic resection of adnexal masses during pregnancy.

OBJECTIVE: To characterize the safety and feasibility of robotic adnexal surgery during pregnancy, and to compare surgical and obstetric outcomes for robotic versus laparoscopic treatment of adnexal masses during pregnancy. STUDY DESIGN: A retrospective cohort study of all cases of robotic resection of adnexal masses in gravid patients performed at our institution between 2006 and 2009 compared with 50 consecutive historic laparoscopic controls performed between 1999 and 2007. RESULTS: During the study period, 19 parturients underwent planned robotic resection of adnexal masses, all of which were uncomplicated. Compared with 50 consecutive laparoscopic controls, no differences in operative time, conversion to laparotomy, intraoperative or postoperative complications, or observed obstetric outcomes were apparent. The robotic cohort had a significantly shorter length of hospital stay (p < 0.01) and estimated blood loss (p = 0.02). CONCLUSION: Robotic resection of adnexal masses during pregnancy appears both safe and feasible, with similar surgical outcomes when compared with a historic laparoscopic cohort.

What Should Students and Trainees Be Taught About Turfing and Where Patients Belong?

Turfing is a colloquialism that refers to what clinicians do to patients whose needs do not fit neatly and tidily into typical clinical placement protocols, especially during inpatient admissions from a hospital's emergency department. This term and this practice are both clinically and ethically problematic because a patient is rarely, if ever, "turfed" to their advantage. Ethically speaking, turfing constitutes deferral of responsibility for a patient's admission or care to colleagues. This article suggests when and under which circumstances it is clinically and ethically appropriate to defer a patient's care and suggests why turfing happens despite its negative influence on both physicians and patients.

Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis.

Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes.

Comparative evaluation of antimicrobial effects of Er:YAG, diode, and CO2 lasers on titanium discs: an experimental study.

PURPOSE: This study examined carbon dioxide (CO(2); 10,600 nm), diode (808 nm), and erbium (Er):yttrium-aluminum-garnet (YAG; 2,940 nm) laser applications on Staphylococcus aureus contaminated, sandblasted, large-grit, acid-etched surface titanium discs and performed a comparative evaluation of the obtained bactericidal effects and the applicability of these effects in clinical practice. MATERIALS AND METHODS: This study was carried out in 5 main groups: Er:YAG laser in very short pulse (VSP) emission mode, Er:YAG laser in short pulse (SP) emission mode, diode laser with a 320-nm fiber optic diode laser with an R24-B handpiece, and CO(2) laser. After laser irradiation, dilutions were spread on sheep blood agar plates and, after an incubation period of 24 hours, colony-forming units were counted and compared with the control group, and the bactericidal activity was assessed in relation to the colony counts. RESULTS: The CO(2) laser eliminated 100% of the bacteria at 6 W, 20 Hz, and a 10-ms exposure time/pulse with a 10-second application period (0.8-mm spot size). The continuous-wave diode laser eliminated 97% of the bacteria at 1 W using a 10-second application with a 320-µm optic fiber, 100% of the bacteria were killed with a 1-W, 10-second continuous-wave application with an R14-B handpiece. The Er:YAG laser eliminated 100% of the bacteria at 90 mJ and 10 Hz using a 10-second application in a superpulse mode (300-ms exposure time/pulse). The Er:YAG laser also eliminated 99% to 100% of the bacteria in VSP mode at 90 mJ and 10 Hz with a 10-second application. CONCLUSIONS: The results of this study show that a complete, or near complete, elimination of surface bacteria on titanium surfaces can be accomplished in vitro using a CO(2), diode, or Er:YAG laser as long as appropriate parameters are used.