Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy.

DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.

Normal Erythroid Precursors in Diamond-Blackfan Anemia: A Rare Case Highlighting Challenges That Remain.

Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome that is both genetically and clinically heterogeneous. The diagnosis of DBA has changed over time, with advancements in our understanding of the varied genetic etiologies and phenotypic manifestations of the disease. We present a rare case of a patient who never developed erythroid precursor hypoplasia, adding to the understanding of atypical manifestations of DBA. Our patient had spontaneous remission followed by subsequent relapse, both atypical and poorly understood processes in DBA. We highlight important considerations in diagnostically challenging cases and review major outstanding questions surrounding DBA.

Passive transfer of alloantibodies through breast milk as a mediator of hemolytic anemia.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is characterized by destruction of fetal/neonatal red blood cells (RBCs) secondary to maternally derived antibodies, which are typically thought to be passively acquired via placental transfer. Few cases have examined the possibility of HDFN mediated by maternal antibodies passively transferred via breast milk. METHODS: We describe two cases of persistent HDFN in infants potentially mediated by passively acquired antibodies via maternal breast milk. We discuss supporting and refuting evidence that may account for this possibility and describe testing methodology illustrating how maternal alloantibodies can be detected in breast milk. RESULTS: In both cases, anti-D antibodies were detected in maternal breast milk. One patient experienced a significant decrease in anti-D plasma titer from 64 to 4 dilutions following 2 weeks of breastfeeding cessation. The other patient experienced a resolution of anemia without breastfeeding cessation. CONCLUSION: There is a paucity of data regarding the lifespan of passively acquired RBC antibodies in neonatal circulation, with significant variation noted between passively acquired IgG based on studies utilizing intravenous immunoglobulin compared to studies of maternally-acquired antiviral IgG antibodies. While our data do not definitively implicate passive transfer of alloantibodies in breast milk as a mediator of HDFN, they do illustrate the need for further investigation into the mechanisms and kinetics of passively acquired antibodies in neonatal circulation.

Engagement with the North Wales Local Dental Committee - part 1: current participation and opinions of its communication methods.

Aims To gather the views of North Wales dentists on the current communication methods of the North Wales Local Dental Committee (LDC) (NWLDC) and how this could be optimised to improve engagement from members.Design Descriptive cross-sectional survey.Setting Online electronic questionnaire.Materials and methods Survey circulated via the NWLDC's current communication channels, local professional groups, the local health board and Health Education and Improvement Wales' Maxcourse distribution list.Results A total of 167 unique responses were received from across North Wales. In total, 79.1% were from dentists, of which most were working in the general dental services (63.6%) on a mixed practice basis (61.9%). Furthermore, 69.5% of respondents felt they received too little information from the LDC, 71.3% never attended LDC meetings and only 15.6% attended more than one meeting a year. The pandemic has had no impact for 82.6% in increasing their engagement with the LDC.Conclusions Communication between the LDC and the dental community within an area is crucial. This survey has shown that, despite the best of intentions, the current communication methods utilised by the NWLDC are not effective at maximising the inclusiveness and participation with the LDC. The survey revealed that there is a lack of clarity over the LDC's role and who is 'allowed' to attend LDC meetings. It showed that although the dental practitioners practising within North Wales want to receive information and updates from the NWLDC, the communication methods which are currently being used are not reaching the majority of them.

Engagement with the North Wales Local Dental Committee - part 2: communication preferences.

Aims To gather the views of dentists practising within North Wales on their preferences as to how they would prefer to interact with the North Wales Local Dental Committee (LDC) (NWLDC).Design Descriptive cross-sectional survey.Setting Online electronic questionnaire.Materials and methods Survey circulated via the NWLDC's current communication channels, local professional groups, the local health board and Health Education and Improvement Wales' MaxCourse email distribution.Results A total of 167 unique responses were received from across North Wales, which included 132 responses from primary care dentists, yielding a response rate of 40.6%. Respondents would prefer to interact with the NWLDC via email notifications (88%), virtual meetings (52.1%) and via the LDC website (41.9%). Furthermore, 31.1% wanted a combination of both physical and virtual attendance at an LDC meeting to be an option and 43.7% of respondents did not want to attend LDC meetings as a preferred method of engaging with the LDC. The survey indicated that holding an educational event just before the LDC meeting will not have a positive impact on subsequent participation in the LDC meeting for 91.6% of respondents. The survey revealed that 70% had never visited the NWLDC's website, with only 20.4% of people visiting it more than once a year. Also, 83.8% stated that the pandemic had made no difference on them accessing the NWLDC website. The results allowed the identification of the top five 'core elements' for an ideal LDC website and which elements should have their access restricted only to LDC members.Conclusions The survey revealed that the respondents want greater communication from the NWLDC and that this is best achieved over a variety of different communication platforms, using the NWLDC website as a primary information resource to which the other communication methods are tethered. It is recognised that only a minority will want to, or be able to, attend the quarterly LDC meetings and so it is imperative that the NWLDC's communication strategy accommodates these individuals, both proactively and passively, by effective use of digital media and to continuously monitor its effectiveness so that it can adapt its strategy to maximise engagement and information delivery. There is a need to expand the representation of the LDC committee to encompass those who have newly entered the profession or are new to the area. The NWLDC recognises the need to reach out to dentists across North Wales who many feel isolated and disenfranchised to establish a constructive, mutually beneficial relationship.

Implementation of an enhanced recovery program for bariatric surgery.

INTRODUCTION: Enhanced recovery after surgery (ERAS) programs have been successfully implemented in several surgical fields; however, there have been mixed results observed in bariatric surgery. Our institution implemented an enhanced recovery program with specific pre-, intra-, and post-operative protocols aimed at patients, nursing staff, and physicians. The aim of the study is to assess the effectiveness of the ERAS program. METHODS: Patients who underwent bariatric surgery prior to the implementation of the enhanced recovery program in the calendar year 2015 were compared to those who had surgery after implementation in 2017. Data for our institution was drawn from the Premier Hospital Database. Poisson and quantile regressions were used to examine the association between ERAS protocol and LOS and cost, respectively. Logistic regression was used to assess the impact of ERAS on 30-day complications and readmissions. RESULTS: 277 bariatric surgical procedures were performed in the pre-ERAS group, compared to 348 procedures post-ERAS. While there was a 25.6% increase in volume, there was no statistical difference between the patient populations or the type of procedure performed between the 2 years. A decrease in length of stay was observed from 2.77 days in 2015 to 1.77 days in 2017 (p < 0.001), while median cost was also cut from $11,739.03 to $9482.18 (p < 0.001). 30-day readmission rate also decreased from 7.94% to 2.86% (p = 0.011). After controlling for other factors, ERAS protocol was associated with decreased LOS (IRR 0.65, p < 0.001), cost (- $2256.88, p < 0.001), and risk of 30-day readmission (OR 0.37, p = 0.011). CONCLUSION: The implementation of a standardized enhanced recovery program resulted in reduced length of stay, cost, and 30-day readmissions. Total costs saved were greater than $800,000 in one calendar year. This study highlights that the value of an enhanced recovery program can be observed in bariatric surgery, benefiting both patients and hospital systems.

Helmets Matter: Kentucky All-Terrain Vehicle Crashes Seen at a Tennessee Trauma Center.

All-terrain vehicle (ATV) safety laws, including helmet use, vary by state and are sporadically enforced. Kentucky state laws require safety helmets only for younger riders. We hypothesized that ATV riders injured in Kentucky and seen at a Tennessee trauma center would more likely be unhelmeted, have more severe head injuries, and have higher mortality rates than those injured in Virginia or Tennessee. A Trauma Registry review of 750 injured ATV riders from June 1, 2005, through June 1, 2015 examined state location of accident, helmet use, markers of injury severity, and outcomes. Multiple logistic regression analysis examined predictors of severe head injuries and death with P < 0.05 significant. Unhelmeted ATV rider status predicted more severe head injuries (relative risk 23.5, P < 0.001) and death (relative risk 4.6, P < 0.001). ATV riders injured in the state of Kentucky were twice as numerous. In addition, they were more likely than ATV riders injured in Tennessee or Virginia to be unhelmeted, to have severe head injuries, and to sustain fatal injuries (all P < 0.001). This single trauma center study lends support for maintaining and enforcing current universal helmet laws for ATV riders of all ages in states where they are in effect and highlights the need to upgrade helmet laws that apply only to some riders.

Helmets Matter: Kentucky Motorcycle Crash Victims Seen at a Tennessee Trauma Center.

OBJECTIVES: Motorcycle helmet laws vary by state, with Kentucky requiring helmets only for younger riders. We hypothesized that motorcyclists injured in Kentucky and seen at a Tennessee trauma center would be more likely to be unhelmeted, have more severe head injuries, and sustain more fatal injuries than those injured in Tennessee or Virginia. METHODS: A Trauma Registry review of 729 injured motorcyclists from January 2005 through June 2015 examined state location of crash, demographics, helmet use, and clinical outcomes. Multivariate logistic regression analysis evaluated predictors for head injury severity and death. RESULTS: Unhelmeted motorcycle rider status predicted more severe head injuries (relative risk 15.3, P < 0.001) and death (relative risk 4.2, P < 0.001). Motorcyclists injured in the state of Kentucky were more likely to be unhelmeted, require an operative procedure, have more severe head injuries, have longer lengths of stay, and sustain more fatal injuries (all with < 0.001) than motorcyclists injured in Tennessee or Virginia. CONCLUSIONS: This study lends support for maintaining and enforcing current universal motorcycle helmet laws for all ages in states where they are in effect and for upgrading helmet laws that apply only to some riders.

Finding an alternative to formalin for sterilization of extracted teeth for teaching purposes.

Formalin is a known carcinogen, so there is a need to establish whether a safer alternative is available for the sterilization of human teeth destined for use in clinical training. Any disinfectant that is not capable of sterilizing 100 percent of the samples tested should be considered a failure. In this study, biofilms of oral bacteria were grown on previously autoclaved extracted human teeth. These biofilm-laden teeth were then screened against a range of disinfectants for an exposure time of seven days in a laboratory refrigerator. Culture methods were employed to validate the sterility of the tooth samples. Five percent Virkon and Gigasept PA proved effective against the laboratory model of disinfection and were carried forward to challenge freshly extracted human teeth. Gigasept PA was the only disinfectant that sterilized 100 percent of the tooth samples. Gigasept PA should be considered a safer and effective alternative to formalin for the sterilization of extracted teeth destined for teaching purposes.