An Icon of Painless Parker.

The discovery of two unaccredited photographs purported to be of Painless Parker occasions a discussion of the notorious "outlaw" dentist's historical significance. It is argued that social media threaten to have performance eclipse clinical skills in dentistry - a process that can be sourced to Parker's vaudevillian antics.

Shift-to-shift handoffs in the NICU: lessons learned from a large scale audit.

OBJECTIVE: Describe the frequency of best practice behaviors during NICU provider and nursing shift-to-shift handoffs and identify strengths and opportunities for improvement. STUDY DESIGN: Observational study of handoff characteristics among 40 centers participating in a learning collaborative over a 10-month period. Data were gathered using a handoff audit tool that outlined best practices. Comparisons of behaviors between nurse-to-nurse and provider-to-provider handoffs were made where appropriate. RESULTS: Overall, 946 audits of shift-to-shift handoffs were analyzed. While many behaviors were demonstrated reliably, differences between nurse-to-nurse vs provider-to-provider handoffs were noted. Families were present for 5.9% of handoffs and, among those who were present, 48.2% participated by contributing information, asking questions, and sharing goals. CONCLUSIONS: Observation and measurement of handoff behaviors can be used to identify opportunities to improve handoff communication, family participation, and human factors that support handoff. Auditing handoffs is feasible and necessary to improve these critical transitions in infants' care.

Post-exposure persistence of nitric oxide upregulation in skin cells irradiated by UV-A.

Evidence suggests that exposure to UV-A radiation can liberate nitric oxide from skin cells eliciting vasodilation in-vivo. However, the duration of nitric oxide release in skin cells after UV exposure is not well studied, with emphasis on UV-B mediated iNOS upregulation. The current study demonstrated persistence of nitric oxide release in a dark reaction after moderate UV-A exposure, peaking around 48 h post exposure; this effect was shown in keratinocytes, fibroblasts and endothelial cells from neonatal donors and keratinocytes from aged donors and confirmed the hypothesis that UV-A exposure appeared to upregulate cNOS alongside iNOS. Release of nitric oxide in the skin cells induced by a moderate exposure to UV-A in sunlight may be especially beneficial for some demographic groups such as the elderly, hypertensive patients or those with impaired nitric oxide function, not only during exposure but many hours and days after that.

Isolation of five different primary cell types from a single sample of human skin.

We have developed a technique to isolate primary keratinocytes, melanocytes, fibroblasts, preadipocytes, and microvascular endothelial cells from an individual sample of human skin. The protocol describes step-by-step instructions for processing, cells isolation, and culture of neonatal foreskin, with adaptation for more demanding adult tissues. The availability of multiple isogenic cell types derived from individual skin samples offers the ability to investigate various areas of biology, in the context of cell-type specificity without potential confounding influence of inter-individual or genetic differences. For complete details on the use and execution of this protocol, please refer to Holliman et al. (2017), Horvath et al. (2019), Horvath et al. (2018), Kabacik et al. (2018), Lowe et al. (2020), Lu et al. (2019), and Lu et al. (2018).

The Stewardship of George Lewis Elliot: Canada's First Dean of Dentistry.

George Lewis Elliot has not been given his proper due as the first dean of dentistry in Canada. Elliot was in the center of a scandal, surrounding his establishment of a private dental school, the Canada College of Dentistry. Faced with a regulatory body whose leaders he perceived to be engaging in the practice "choking off" and "stamping out" their competitors, Elliot undertook to create an independent dental school to provide prospective licentiates with the means to pass the board exams, thereby also improving the profession.

Amnioreduction with rescue cerclage at advanced cervical dilation or gestational age.

OBJECTIVE: To determine the feasibility of rescue cerclage and amnioreduction at advanced cervical dilation or gestational age. METHODS: We present a retrospective case series of women who underwent rescue cerclage at either an advanced gestational age (24 + 0 to 24 + 6 weeks) or cervical dilation (≥4 cm), with a subset undergoing amnioreduction prior to cerclage placement. RESULTS: Nine women were included and amnioreduction was performed in 7 (78%). A bi-modal distribution of obstetric outcomes was observed, with 5 (56%) women delivering ≥34 weeks gestation, 3 (33%) of which delivered at term. Two (22%) women experienced intra-operative rupture of membranes and subsequent perinatal deaths. Two (22%) women delivered extremely premature, with one resulting in infant death. DISCUSSION: Our data show that rescue cerclage with amnioreduction may be successful at advanced gestational ages or cervical dilations, suggesting that these women should be included in prospective studies to better establish the efficacy and safety of this procedure.

The relationship between epigenetic age and the hallmarks of aging in human cells.

Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells1,2. The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors2, indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified3. We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.

Variability in the systems of care supporting critical neonatal intensive care unit transitions.

OBJECTIVE: Assess practices supporting care transitions for infants and families in the neonatal intensive care unit (NICU) using a model of four key drivers: communication, teamwork, family integration, and standardization. STUDY DESIGN: Single-day audit among NICUs in the Vermont Oxford Network Critical Transitions collaborative addressing policies and practices supporting the four key drivers during admission, discharge, shift-to-shift handoffs, within hospital transfers, and select changes in clinical status. RESULTS: Among 95 NICUs, the median hospital rate of audited policies in place addressing the four key drivers were 47% (inter-quartile range (IQR) 35-65%) for communication, 67% (IQR 33-83%) for teamwork, 50% (IQR 33-61%) for family integration, and 70% (IQR 56-85%) for standardization. Of the 2462 infants included, 1066 (43%) experienced ≥1 specified transition during the week prior to the audit. CONCLUSIONS: We identified opportunities for improving NICU transitions in areas of communication, teamwork, family integration, and standardization.

Evaluation of artificial intelligence-based telemedicine screening for retinopathy of prematurity.

Retrospective evaluation of a deep learning-derived retinopathy of prematurity (ROP) vascular severity score in an operational ROP screening program demonstrated high diagnostic performance for detection of type 2 or worse ROP. To our knowledge, this is the first report in the literature that evaluated the use of artificial intelligence for ROP screening and represents a proof of concept. With further prospective validation, this technology might improve the accuracy, efficiency, and objectivity of diagnosis and facilitate earlier detection of disease progression in patients with potentially blinding ROP.

Chronic irradiation of human cells reduces histone levels and deregulates gene expression.

Over the past decades, there have been huge advances in understanding cellular responses to ionising radiation (IR) and DNA damage. These studies, however, were mostly executed with cell lines and mice using single or multiple acute doses of radiation. Hence, relatively little is known about how continuous exposure to low dose ionising radiation affects normal cells and organisms, even though our cells are constantly exposed to low levels of radiation. We addressed this issue by examining the consequences of exposing human primary cells to continuous ionising γ-radiation delivered at 6-20 mGy/h. Although these dose rates are estimated to inflict fewer than a single DNA double-strand break (DSB) per hour per cell, they still caused dose-dependent reductions in cell proliferation and increased cellular senescence. We concomitantly observed histone protein levels to reduce by up to 40%, which in contrast to previous observations, was not mainly due to protein degradation but instead correlated with reduced histone gene expression. Histone reductions were accompanied by enlarged nuclear size paralleled by an increase in global transcription, including that of pro-inflammatory genes. Thus, chronic irradiation, even at low dose-rates, can induce cell senescence and alter gene expression via a hitherto uncharacterised epigenetic route. These features of chronic radiation represent a new aspect of radiation biology.

Patient-Centered Standards for Medically Integrated Dispensing: ASCO/NCODA Standards.

PURPOSE: To provide standards for medically integrated dispensing of oral anticancer drugs and supportive care medications. METHODS: An Expert Panel was formed, and a systematic review of the literature on patient-centered best practices for the delivery of oral anticancer and supportive care drugs was performed to April 2019 using PubMed and Google Scholar. Available patient-centered standards, including one previously developed by the National Community Oncology Dispensing Association (NCODA), were considered for endorsement. Public comments were solicited and considered in preparation of the final manuscript. RESULTS: A high-quality systematic review that was current to May 2016 was adopted into the evidence base. Five additional primary studies of multifaceted interventions met the inclusion criteria. These studies generally included a multicomponent intervention, often led by an oncology pharmacist, and also included patient education and regular follow-up and monitoring. These interventions resulted in significant improvements to patient quality and safety and demonstrated improvements in adherence and other patient outcomes. CONCLUSION: The findings of the systematic review were consistent with the NCODA patient-centered standards for patient relationships and education, adherence, safety, collection of data, documentation, and other areas. NCODA standards were adopted and used as basis for these American Society of Clinical Oncology/NCODA standards. Additional information is available at www.asco.org/mid-standards.

Early fortification of enteral feedings for infants <1250 grams birth weight receiving a human milk diet including human milk based fortifier.

BACKGROUND: An exclusive human milk diet (EHM) including fortification with a human milk-based fortifier has been shown to decrease the occurrence of necrotizing enterocolitis (NEC) but growth velocity may be less for infants receiving EHM compared to a bovine diet. OBJECTIVE: The objective of this study was to determine if growth is improved by earlier fortification of breast milk for preterm infants supported with a human milk based fortifier. STUDY DESIGN: A multi-center retrospective cohort study of the outcomes of infants of 500- 1250 g birth weight whose breast milk feedings were fortified at >60 mL/kg/day (late) versus <60 mL/kg/day (early) of enteral feeding volume. RESULTS: Median±IQR range for gestational age (27.6±3.4 vs 27.0±2.9 weeks, p = 0.03) and chronic lung disease (CLD: 42.6 vs 27.6%, p = 0.008) were higher, and weight gain (12.9±2.6 vs 13.3±2.6 g/kg/day, p = 0.03) was lower in the late (N = 102) vs the early (N = 292) group. Adjusted multiple linear regression analysis found that early fortification was associated with improved growth velocity for weight (p = 0.007) and head circumference (HC) (p = 0.021) and less negative changes in z-scores for weight (p = 0.022) and HC (p = 0.046) from birth to discharge. Adjusted multiple logistic regression found that early fortification was associated with decreased occurrence of CLD (p = 0.004). No other outcomes, including NEC, were associated with early versus late fortification. CONCLUSION: The study results suggested that early HM fortification appears to positively affect growth for infants whose human milk feedings are fortified with a human milk based fortifier without adverse effects. The incidence of CLD was also reduced in the early fortification group.

Reuben J. Silver (1924-2018).

Reuben J. Silver passed away on April 11, 2018, in Wilmington, North Carolina, his home for the last 18 years. He was born to Hyman Jonah Silver and Shaynah Volk Silver in Medway, Massachusetts, on September 12, 1924. Reuben was nationally recognized for his contributions to the professional practice of psychology. Many of his contributions were made when legal recognition for psychology was still in its infancy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation.

The advent of epigenetic clocks has prompted questions about the place of epigenetic ageing within the current understanding of ageing biology. It was hitherto unclear whether epigenetic ageing represents a distinct mode of ageing or a manifestation of a known characteristic of ageing. We report here that epigenetic ageing is not affected by replicative senescence, telomere length, somatic cell differentiation, cellular proliferation rate or frequency. It is instead retarded by rapamycin, the potent inhibitor of the mTOR complex which governs many pathways relating to cellular metabolism. Rapamycin, however, is also an effective inhibitor of cellular senescence. Hence cellular metabolism underlies two independent arms of ageing - cellular senescence and epigenetic ageing. The demonstration that a compound that targets metabolism can slow epigenetic ageing provides a long-awaited point-of-entry into elucidating the molecular pathways that underpin the latter. Lastly, we report here an in vitro assay, validated in humans, that recapitulates human epigenetic ageing that can be used to investigate and identify potential interventions that can inhibit or retard it.

Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression.

The paramount role of senescent cells in ageing has prompted suggestions that re-expression of telomerase may prevent ageing; a proposition that is predicated on the assumption that senescent cells are the sole cause of ageing. Recently, several DNA methylation-based age estimators (epigenetic clocks) have been developed and they revealed that increased epigenetic age is associated with a host of age-related conditions, and is predictive of lifespan. Employing these clocks to measure epigenetic age in vitro, we interrogated the relationship between epigenetic ageing and telomerase activity. Although hTERT did not induce any perceptible change to the rate of epigenetic ageing, hTERT-expressing cells, which bypassed senescence, continued to age epigenetically. Employment of hTERT mutants revealed that neither telomere synthesis nor immortalisation is necessary for the continued increase in epigenetic age by these cells. Instead, the extension of their lifespan is sufficient to support continued epigenetic ageing of the cell. These characteristics, observed in cells from numerous donors and cell types, reveal epigenetic ageing to be distinct from replicative senescence. Hence, while re-activation of hTERT may stave off physical manifestation of ageing through avoidance of replicative senescence, it would have little impact on epigenetic ageing which continues in spite of telomerase activity.

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies.

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

Ultraviolet Radiation-Induced Production of Nitric Oxide:A multi-cell and multi-donor analysis.

Increasing evidence regarding positive effects of exposure to sunlight has led to suggestions that current advice may be overly weighted in favour of avoidance. UV-A has been reported to lower blood pressure, possibly through nitric oxide (NO) production in skin. Here, we set out to investigate effects of UV-A and solar-simulated radiation on the potential source of dermal NO, the effective doses and wavelengths, the responsiveness of different human skin cells, the magnitude of inter-individual differences and the potential influence of age. We utilised isogenic keratinocytes, microvascular endothelial cells, melanocytes and fibroblasts isolated from 36 human skins ranging from neonates to 86 years old. We show that keratinocytes and microvascular endothelial cells show greatest NO release following biologically relevant doses of UV-A. This was consistent across multiple neonatal donors and the effect is maintained in adult keratinocytes. Our observations are consistent with a bi-phasic mechanism by which UV-A can trigger vasodilatory effects. Analyses of NO-production spectra adds further evidence that nitrites in skin cells are the source of UV-mediated NO release. These potentially positive effects of ultraviolet radiation lend support for objective assessment of environmental influence on human health and the idea of "healthy sun exposure".

Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory.

OBJECTIVES: The aim of this study was to create and validate severity levels for the central sensitization inventory (CSI), a valid and reliable patient-reported outcome instrument designed to identify patients whose presenting symptoms may be related to a central sensitivity syndrome (CSS; eg, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome), with a proposed common etiology of central sensitization (CS). METHODS: Based on CSI score means and standard deviations from previously published subject samples, the following CSI severity levels were established: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100. The concurrent validity of the CSI severity levels was then confirmed in a separate chronic pain patient sample (58% with a CSS diagnosis and 42% without) by demonstrating associations between CSI scores and (1) the number of physician-diagnosed CSSs; (2) CSI score distributions in both CSS and non-CSS patient samples; (3) patient-reported history of CSSs; and (4) patient-reported psychosocial measures, which are known to be associated with CSSs. RESULTS: Compared to the non-CSS patient subsample, the score distribution of the CSS patient subsample was skewed toward the higher severity ranges. CSI mean scores moved into higher severity levels as the number of individual CSS diagnoses increased. Patients who scored in the extreme CSI severity level were more likely to report previous diagnoses of fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, tension/migraine headaches, and anxiety or panic attacks (P < 0.01). CSI severity levels were also associated with patient-reported depressive symptoms, perceived disability, sleep disturbance, and pain intensity (P ≤ 0.02). CONCLUSION: This study provides support for these CSI severity levels as a guideline for healthcare providers and researchers in interpreting CSI scores and evaluating treatment responsiveness.

Sex Differences in Fractional Flow Reserve-Guided Revascularization: A Nationwide Analysis.

BACKGROUND: Women with coronary artery disease are less likely to be revascularized than men based on angiography alone. Recent studies have shown that female patients have higher fractional flow reserve (FFR) values for a given severity of coronary stenosis. However, gender differences in coronary revascularization rates following FFR assessment are unknown. METHODS: The nationwide inpatient sample database was used to identify all patients who underwent FFR in the United States between January 2009 and December 2010. We used propensity score matching to compare revascularization rates and in-hospital outcomes among men and women undergoing FFR measurements. RESULTS: Among 3712 patients who underwent FFR during the study period, 1235 matched pairs of men and women were identified. The overall revascularization rates were lower in women than men (40.1% vs. 52.8%, p < 0.01). Women were less likely to undergo either percutaneous (35.2% vs. 45.6%, p < 0.01) or surgical revascularization following FFR than men (5.2% vs. 7.4%, p = 0.03). Women had a nonsignificant trend toward higher in-hospital mortality (0.8% vs. 0.5%, p = 0.32) and significantly higher rates of access site hematoma formation (2.7% vs. 0.8%, p < 0.01) compared to men. CONCLUSION: In conclusion, this large nationwide study reveals that coronary revascularization rates are significantly lower in women than in men even after functional assessment with FFR.

Pericardiocentesis Under Continuous Ultrasonographic Guidance Using a 7 cm Micropuncture Needle.

OBJECTIVES: To compare procedural success and safety of pericardiocentesis using continuous ultrasonographic visualization of a long (7 cm) micropuncture needle to standard access with an 18 gauge needle without continuous ultrasound guidance. BACKGROUND: Current approaches to pericardiocentesis commonly utilize a large-bore 18 gauge needle for access without allowing for continuous visualization of needle entry into the pericardial space. METHODS: We included all consecutive patients at our institution who underwent pericardiocentesis between November 1, 2011 and March 3, 2016. A total of 21 patients (group 1) underwent pericardiocentesis using a 7 cm micropuncture needle inserted under continuous ultrasonographic guidance, while 51 patients (group 2) underwent pericardiocentesis, mostly with an 18 gauge needle (92%), following preprocedural echocardiography only. The primary endpoint was successful placement of a drain into the pericardial space. RESULTS: The primary endpoint was similar between group 1 and group 2 (100% vs 94%, respectively; P=.26). Successful drainage of pericardial fluid was achieved in 95% of patients in group 1 and in 98% in group 2 (P=.88). The amount of pericardial fluid drained in each group was similar (640 mL vs 557 mL, respectively; P=.26). No procedure-related complications occurred in group 1, compared with 2 cases of right ventricular perforation that occurred in group 2. In-hospital mortality and length of stay were similar. CONCLUSION: This study suggests that an ultrasound-mounted micropuncture needle allows for safe and effective pericardiocentesis. This technique may provide a safer alternative to the standard use of an 18 gauge needle.