Pandemic-Era Digital Education: Insights from an Undergraduate Medical Programme.

The undergraduate medical programme at Newcastle University (NU) includes a fundamental 'Essentials of Medical Practice' (EOMP) phase comprising the first 2 years of study. This period is designed to support entrants in their transition from further education into the advanced study and practice of clinical medicine. The anatomical sciences of gross anatomy, histology and embryology, and life sciences including physiology, pharmacology and genetics are key disciplines taught within the integrated case-based EOMP curriculum. Learners apply basic science knowledge to clinical scenarios during training in practical examination, communication and reasoning skills. Within the modern pedagogic landscape, the development and introduction of technology-enhanced learning strategies have enhanced the provision of remote learning resources in pre-clinical education. However, the emergence of COVID-19 has resulted in widespread technological challenges for educators and learners, and has raised pedagogic, logistical and ethical concerns. Nonetheless, the pandemic has produced favourable conditions for the creation of valuable digital visualisation strategies for learning and teaching, and for developing and modernising universal approaches to remote education. Here, we describe our technology-enhanced adaptations to COVID-19 across the domains of teaching, learning and academic support for pre-clinical learners studying basic life sciences and clinical skills. Moreover, we outline research-informed digital visualisation solutions to pandemic-era challenges and reflect upon experiences gained within our own educational context. In doing so, we provide insights into the impacts and successes of our interventions. While providing a record of unprecedented contemporary circumstances, we also aim to utilise our observations and experiences of COVID-19 pedagogy when developing ongoing strategies for delivering curricula and futureproofing educational practice.

A Cross-Sectional Descriptive Analysis of Speech, Hearing, and Feeding in YouTube Videos: A Brief Communication.

OBJECTIVE: Healthcare information on YouTube is often inaccurate or insufficient. However, parents turn to social media for answers about their children's health conditions. Understanding the nature of content in specified scope of practice areas can help professionals clarify misinformation or utilize quality YouTube content in clinical context. This research examined: (1) meta-data and upload source; (2) understandability and actionability; and (3) content quality and clinical utility of YouTube videos related to speech, hearing, and feeding with children with cleft lip and palate (CLP). DESIGN: A cross-sectional design was used. MAIN OUTCOME MEASURE(S): Videos related to speech, hearing, and feeding with children with CLP were obtained. Meta-data and upload source were identified. The Patient Education Material Assessment Tool-AudioVisual (PEMAT-AV) was used to assess understandability and actionability. The DISCERN instrument was used to evaluate content quality. Responses to open-ended questions were used to evaluate clinical utility. RESULTS: Of 652 videos reviewed for potential inclusion, only 33 met the inclusion criteria. Of those, only 17 met adequate levels of both understandability and actionability. Results of DISCERN indicated that the videos were of fair quality. Analysis of clinical utility indicated that none of the videos should be used as stand-alone parent education materials. CONCLUSIONS: Videos pertaining to speech, hearing and feeding issues are not viewed as frequently as videos addressing other areas of CLP. Our findings are consistent with previous reports that the videos related to CLP may be limited in their clinical utility. Professionals are needed to interpret the offerings and guide families to appropriate videos.

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases.

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.

2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2.

Prolyl hydroxylation of hypoxia inducible factor (HIF)-α, as catalysed by the Fe(ii)/2-oxoglutarate (2OG)-dependent prolyl hydroxylase domain (PHD) enzymes, has a hypoxia sensing role in animals. We report that binding of prolyl-hydroxylated HIF-α to PHD2 is ∼50 fold hindered by prior 2OG binding; thus, when 2OG is limiting, HIF-α degradation might be inhibited by PHD binding.

Lysine-241 Has a Role in Coupling 2OG Turnover with Substrate Oxidation During KDM4-Catalysed Histone Demethylation.

The JmjC histone lysyl demethylases (KDMs) play important roles in modulating histone methylation states and have the potential to be regulated by oxygen availability. Lys241 of the KDM4 subfamily is proposed to be important in oxygen binding by KDM4A. We report evidence that, although Lys241 is unlikely to be directly involved in oxygen binding, it has an important role in coupling 2-oxoglutarate cosubstrate oxidation with lysine demethylase activity. The results suggest that compounds promoting the uncoupling of substrate oxidation are of interest as JmjC-KDM inhibitors.

Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates.

Methylation of lysine-4 of histone H3 (H3K4men) is an important regulatory factor in eukaryotic transcription. Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. Altered levels of tricarboxylic acid (TCA) cycle intermediates and the associated metabolites D- and L-2-hydroxyglutarate (2HG) can cause changes in chromatin methylation status. We report comprehensive biochemical, structural and cellular studies on the interaction of TCA cycle intermediates with KDM5B, which is a current medicinal chemistry target for cancer. The tested TCA intermediates were poor or moderate KDM5B inhibitors, except for oxaloacetate and succinate, which were shown to compete for binding with 2OG. D- and L-2HG were moderate inhibitors at levels that might be relevant in cancer cells bearing isocitrate dehydrogenase mutations. Crystallographic analyses with succinate, fumarate, L-malate, oxaloacetate, pyruvate and D- and L-2HG support the kinetic studies showing competition with 2OG. An unexpected binding mode for oxaloacetate was observed in which it coordinates the active site metal via its C-4 carboxylate rather than the C-1 carboxylate/C-2 keto groups. Studies employing immunofluorescence antibody-based assays reveal no changes in H3K4me3 levels in cells ectopically overexpressing KDM5B in response to dosing with TCA cycle metabolite pro-drug esters, suggesting that the high levels of cellular 2OG may preclude inhibition. The combined results reveal the potential for KDM5B inhibition by TCA cycle intermediates, but suggest that in cells, such inhibition will normally be effectively competed by 2OG.

The Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations.

The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations. Here, we report detailed analysis of the effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, importantly demonstrating a high level of O2 sensitivity both with isolated protein and in cells. Kinetic analysis of the recombinant enzyme revealed a high KMapp(O2) of 173 ± 23 µM, indicating that the activity of the enzyme is able to respond sensitively to a reduction in oxygen concentration. Furthermore, immunofluorescence experiments in U2OS cells conditionally overexpressing KDM4A showed that the cellular activity of KDM4A against its primary substrate, H3K9me3, displayed a graded response to depleting oxygen concentrations in line with the data obtained using isolated protein. These results suggest that KDM4A possesses the potential to act as an oxygen sensor in the context of chromatin modifications, with possible implications for epigenetic regulation in hypoxic disease states. Importantly, this correlation between the oxygen sensitivity of the catalytic activity of KDM4A in biochemical and cellular assays demonstrates the utility of biochemical studies in understanding the factors contributing to the diverse biological functions and varied activity of the 2OG oxygenases.

Targeting Protein-Protein Interactions in the HIF System.

Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein-protein and protein-nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein-protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.

Comparing treatment fidelity between study arms of a randomized controlled clinical trial for stroke family caregivers.

OBJECTIVE: To compare treatment fidelity among treatment arms in the Telephone Assessment and Skill-Building Kit study for stroke caregivers (TASK II) with respect to: 1) protocol adherence; 2) intervention dosage and 3) nurse intervener perspectives. DESIGN: A randomized controlled clinical trial design. SETTING: Urban, community, midwestern United States. SUBJECTS: A total of 254 stroke caregivers (mean ±SD age, 54.4 ±11.8 years), 55 (22.0%) males and 199 (78.4%) females) randomized to the TASK II intervention (n=123) or an Information, Support, and Referral comparison group (n=131). INTERVENTIONS: TASK II participants received the TASK II Resource Guide; Information, Support, and Referral participants received a standard caregiver brochure. At approximately 8 weeks after discharge, both groups received 8 weekly calls from a nurse, with a booster call 4 weeks later. MEASURES: Protocol adherence was evaluated with the TASK II Checklist for Monitoring Adherence. Intervention dosage was measured by the number of minutes caregivers spent reading materials and talking with the nurse. Nurse intervener perspectives were obtained through focus groups. RESULTS: Protocol adherence was 80% for the TASK II and 92% for the Information, Support, and Referral. As expected, intervention dosage differed between TASK II and Information, Support, and Referral with respect to caregiver time spent reading materials (t=-6.49; P<.001) and talking with the nurse (t=-7.38; P<.001). Focus groups with nurses yielded further evidence for treatment fidelity and recommendations for future trials. CONCLUSIONS: These findings substantiate treatment fidelity in both study arms of the TASK II stroke caregiver intervention trial (NIH R01NR010388; ClinicalTrials.govNCT01275495).

Epigenetic regulation by histone demethylases in hypoxia.

The response to hypoxia is primarily mediated by the hypoxia-inducible transcription factor (HIF). Levels of HIF are regulated by the oxygen-sensing HIF hydroxylases, members of the 2-oxoglutarate (2OG) dependent oxygenase family. JmjC-domain containing histone lysine demethylases (JmjC-KDMs), also members of the 2OG oxygenase family, are key epigenetic regulators that modulate the methylation levels of histone tails. Kinetic studies of the JmjC-KDMs indicate they could also act in an oxygen-sensitive manner. This may have important implications for epigenetic regulation in hypoxia. In this review we examine evidence that the levels and activity of JmjC-KDMs are sensitive to oxygen availability, and consider how this may influence their roles in early development and hypoxic disease states including cancer and cardiovascular disease.

Hip fractures in people with idiopathic Parkinson's disease: incidence and outcomes.

The incidence of hip fracture and outcomes from hip surgery for people with Parkinson's disease (PD) are thought to be poorer than for people without PD. The aim of this audit of a prospective hip-fracture database was to establish the incidence of, and outcomes from, hip fracture in people with and without PD living in North East England. The number of people with PD living in the study area was estimated using data from two previous prevalence studies in the same geographical area. Using data collected prospectively for the National Hip Fracture Database for Northumbria Healthcare National Health Service Foundation Trust in the UK, the annual incidence of hip fracture in people with and without PD was calculated. Type of fracture, time to surgery, time to discharge, and 30-day outcomes from surgery were compared. Annual incidence of hip fracture was significantly higher in people with PD across all age bands. In those 60 years of age and over, it was 2,171 (95% confidence interval [CI]: 2,082-2,264) per 100,000 in people with PD and 551 (95% CI: 506-598) in people without PD. The experience of PD and non-PD patients within hospital was remarkably similar. However, PD patients had poorer mobility before hip fracture, took longer to be discharged to the community, and were less mobile postsurgery. Specific guidelines for managing people with PD who sustain a hip fracture may help to improve awareness of the potential complications of the condition and improve outcomes.

International practices in the provision of teratology information: a survey of international teratogen information programmes and comparisons with the North American model.

RATIONALE, AIMS AND OBJECTIVES: Teratology Information Services (TIS) provide health care professionals and the public with information regarding the safety and/or risk of exposures during pregnancy and lactation, mainly via telephone consultations. An international comparison of clinical practices at TIS has never been conducted. The survey objective was to compare international TIS to North American TIS, with an aim to identify strengths and challenges that can lead to service improvement. METHODS: Twenty-two international TIS were approached for participation during an international conference. TIS were surveyed on information in six categories: services, staffing, operations, data collection, knowledge transfer activities and additional information. Data were summarized using descriptive statistics. Statistical tests were conducted using SPSS®. RESULTS: Sixteen TIS from 12 countries participated. Survey results were compared with previously reported results from a similar survey of North American TIS (16 US, two Canadian). TIS exist in a variety of departments and settings, but most commonly are in university hospitals. Pregnant women were the most commonly counselled group worldwide. International TIS spent significantly more time fielding inquiries regarding medications, while North American TIS had a wider variety of inquiry categories. All TIS could improve budget tracking. CONCLUSIONS: Overall, service practices and goals were similar, although international TIS conducted more follow-up with service users than North American TIS. This report offers TIS the first ever opportunity to compare practices. Increased dialogue between TIS encourages sharing of best practices and improves the ability of these important public health programmes to support women and health care providers.

Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.

BACKGROUND: Sucrose is widely used to manage procedural pain in term newborns despite a lack of evidence of its effectiveness for different procedures and infant populations. Our objectives were to evaluate the effectiveness and safety of sucrose in newborns undergoing various medical procedures within 2 days of birth. METHODS: We performed a double-blind, randomized controlled trial. We included newborns (>or= 36 weeks gestation) of diabetic mothers and nondiabetic mothers. Each newborn received 2 mL of a 24%-sucrose or placebo solution before all procedures. We used the Premature Infant Pain Profile to assess pain during intramuscular injection of vitamin K, venipuncture for the newborn screening test and the first 3 heel lances for glucose monitoring (newborns of diabetic mothers only). Scores ranged from from 0 (no pain) to 18 (maximum pain). RESULTS: We included 240 newborns (120 from diabetic mothers, 120 from nondiabetic mothers). The overall mean pain score was lower among newborns who received sucrose than among those who received a placebo (mean difference -1.3, 95% confidence interval [CI] -2.0 to -0.6). We found that pain scores during intramuscular injection did not differ significantly between the sucrose and placebo groups for newborns of diabetic or nondiabetic mothers (newborns of nondiabetic mothers: mean difference -1.1, 95% CI -2.4 to 0.2; newborns of diabetic mothers: mean difference -1.0, 95% CI -2.4 to 0.4). During venipuncture, newborns who received sucrose had lower pain scores compared with those who received a placebo (newborns of nondiabetic mothers: mean difference -3.2, 95% CI -4.6 to -1.8; newborns of diabetic mothers: mean difference -2.4, 95% CI -3.8 to -1.0). Among newborns of diabetic mothers, there was no difference in pain during the first 3 heel lances or mean glucose levels between the sucrose and placebo groups (p = 0.94 and p = 0.29 respectively). INTERPRETATION: We found a modest reduction of pain in newborns of both diabetic and nondiabetic mothers when sucrose was used for all medical procedures performed in the first 2 days after birth. However, when each procedure was analyzed separately, we found that the effectiveness of sucrose was limited to venipuncture for the newborn screening test. (http://Clinicaltrials.gov trial register no. NCT00213213.).

Providing information regarding exposures in pregnancy: a survey of North American Teratology Information Services.

PURPOSE: Teratology Information Services (TIS) provide information on exposures during pregnancy and breast-feeding. Maintaining ongoing funding is a challenge. The purpose was to gather descriptive information on current TIS operations. METHODS: All North American TIS (16 American, 2 Canadian) completed a detailed survey. RESULTS: Service goal ranked as most important was correction of risk misperceptions. Inquiries were primarily for medications (mean 43.5%, S.D. 14.1), lactation exposures, and workplace exposures. Median employees per TIS: three (range 1-12.5). Two TIS only counsel health care professionals (HCPs). Main callers to remaining TIS were pregnant women (mean 46.8%, S.D. 22.8), physicians, and nurses. Calls per week varied (median 20, range 4-600). Median annual budget: US dollars 69,000 (range dollars 3000-335,000). Seventeen TIS collect patient data for research. CONCLUSIONS: This survey was the first to document TIS operations in North America and demonstrates a spectrum of clinical and research activities, and provides data for a future cost-benefit analysis of TIS.

Topical amethocaine gel 4% for intramuscular injection in term neonates: a double-blind, placebo-controlled, randomized trial.

BACKGROUND: Topical local anesthetic agents such as amethocaine penetrate intact skin and block pain signals originating from the dermis during medical procedures. They have been found to attenuate pain from various procedures, including intramuscular (i.m.) injection of vaccines. Published data on their effectiveness for i.m. injection of vitamin K in neonates were not identified. OBJECTIVES: The primary objective of this study was to evaluate the analgesic effectiveness and tolerability of topical amethocaine gel 4% in neonates undergoing i.m. injection of vitamin K. The secondary objective was nurses' response to the use of the intervention and possible barriers associated with its incorporation into clinical practice. METHODS: In a double-blind, placebo-controlled, randomized trial, full-term neonates in the Labor and Delivery Unit of Mount Sinai Hospital, Toronto, Ontario, Canada, received 1 g of amethocaine gel 4% or placebo 30 minutes prior to i.m. injection of 0.5 mL of vitamin K. Pain responses were assessed using percent facial grimacing score, percent cry duration, and latency to cry from video recordings. Parents and nurses assessed infants' pain response using a visual analog scale (VAS). Local adverse events (ie, erythema, blanching) at the application site were recorded. Nurses were asked to provide written responses regarding their willingness to incorporate local anesthetics in clinical practice and barriers to their use. RESULTS: From July 2003 to December 2004, 175 families were approached for participation in the study; 52 declined consent and 13 were not randomized. One hundred ten neonates were enrolled and evenly randomized to each group. Baseline characteristics were similar in both groups. During i.m. injection, the mean (SD) percent facial grimacing score was 70% (30%) for the amethocaine group compared with 75% (34%) for the placebo group (P = 0.41). The mean (SD) for percent cry duration was 55% (34%) compared with 62% (38%), respectively (P = 0.34). The mean (SD) latency to cry was significantly longer in the amethocaine group compared with the placebo group (4.7 [4.5] vs 2.7 [2.3] seconds; P = 0.01). Parents' and nurses' VAS ratings for infant pain did not differ between groups. The incidence of adverse events did not differ between groups. Ninety-seven percent of nurses (89/92) said they would use the intervention. Fifty-seven percent of nurses (52/92) identified barriers to incorporation with the primary reason being time constraint (67% [35/52]). CONCLUSIONS: Topical amethocaine gel 4% was ineffective in reducing pain on i.m. injection of vitamin K in these full-term neonates. Treatment was generally well tolerated and nurses concluded that, given the choice, they would use a topical anesthetic.

Dopamine D1 receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 microg/0.5 microl/side) of a D1 DA receptor agonist, SKF 38393, or a D2 DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats.