Reversible Photochromism of 4,4'-Disubstituted 2,2'-Bipyridine in the Presence of SO3.

We report an unusual photochromic behavior of 4,4'-disubstituted-2,2'-bipyridine. It was found that in the presence of a SO3 source and HCl, 2,2'-bipyridine-4,4'-dibutyl ester undergoes a color change from yellow to magenta in solution with maximum absorbance at 545 nm upon irradiation with 395 nm light. The photochromism is thermally reversible in solution. Different from the known bipyridine-based photoswitching pathways, the photo response does not involve any metal which form colored complexes or the formation of colored free radical cations like the photo-reduction of viologens. A combination of experimental and computational analysis was used to probe the mechanism. The results suggest the colored species to be a complex formed between N-oxide of the 2,2'-bipyridine-4,4'-dibutyl ester and SO2; the N-oxide and SO2 are formed from photoactivated oxidation of the bipyridine with SO3 serving as the oxygen source. This complex represents a new addition to the library of photoswitches that is easy to synthesize, reversible in solution, and of high fatigue resistance, making it a promising candidate for applications in photo-switchable materials and SO3 detection. We also demonstrated experimentally similar photochromic behaviors with 2,2'-bipyridine-containing polymers.

Evaluating the Impact of Telehealth on Carbon Footprint During Three Phases of the Pandemic at a Rural Academic Medical Center.

Background: Climate change is primarily driven by greenhouse gases, such as carbon dioxide (CO2). Telehealth visits have been found to mitigate carbon emissions by reducing patient and physician transport. Dartmouth Hitchcock Medical Center (DHMC) is the most rural academic medical center in the country, serving a population where the majority of patients reach the hospital by car. No large study or systematic review has evaluated the impact of telehealth visits on CO2 emissions (CO2e) across multiple specialties in a purely rural setting. Further, no sizable rurally focused study has compared CO2e avoided during the various stages of the pandemic. Methods: We extracted data for all outpatient telehealth visits at DHMC from three periods: prepandemic, early pandemic, and late pandemic. The extracted data included the pandemic stage of the virtual visit, the type of visit (video or telephone), the specialty, and the distance from the patient's home to DHMC. Results: The total CO2e avoided among all three pandemic stages analyzed in this study was 23,658,898 kg (n = 251,832). During period 1, the mean driving distance = 159.0 miles; CO2e avoided per encounter = 128.3 kg; period 2, mean distance = 84.85 miles; average CO2e avoided per encounter = 68.47 CO2e kg; and period 3, mean distance = 112.9 miles; average CO2e avoided per encounter = 91.08 kg. Conclusions: This data supported long distances to the medical center and large savings in CO2e avoided across multiple specialties that spanned all pandemic periods. Further, this level of averted emissions could translate to over $3M in saved fuel costs and the avoidance of six excess deaths. While discussions of the future of telehealth commonly focus on access, use cases, technology, costs, and satisfaction, the impact on carbon footprint is an additional important metric, particularly in largely rural regions.

Novel Triangulenes: Computational Investigations of Energy Thresholds for Photocatalytic Water Splitting.

Organic materials with Inverted Singlet-Triplet (INVEST) gaps are interesting for their potential use in photocatalytic small molecule transformations such as the entirely solar-driven water splitting reaction. However, only a few INVEST emitters are thermodynamically able to split water requiring a first singlet excited dark state, S1 , above 1.27 or 1.76 eV, and absorption near solar the maximum, 2.57 eV. These requirements and the INVEST character are key for achieving a long-lived photocatalyst for water splitting. The only known INVEST emitters that conform to these criteria are large triangular boron carbon nitrides with unknown synthesis pathways. Using ADC(2), a quantum-mechanical method, we describe three triangulenes. 3 a is a cyano azacyclopenta[cd]phenalene derivative while 3 b and 3 c are cycl[3.3.3]azine derivatives. 3 b has a previously undescribed disulfide bridge. Overall, 3 a fulfills requirements for photocatalytic four-electron reduction of water while the S1 states of 3 b and 3 c are likely slightly low for the two-electron reduction process. By analyzing impacts of ligands, we find that there are guidelines describing how S1 -S5 energies and oscillator strengths, T1 energies, and ΔES1T1 gaps are affected, requiring deep-learning algorithms for which studies will be presented by us in due time. The impact of ground-state geometries, solvation effects, as well as reduced-cost ADC(2) algorithms on our findings are also discussed.

Building on the strengths of a double-hybrid density functional for excitation energies and inverted singlet-triplet energy gaps.

It is demonstrated that a double hybrid density functional approximation, ωB88PTPSS, that incorporates equipartition of density functional theory and the non-local correlation, however with a meta-generalized gradient approximation correlation functional, as well as with the range-separated exchange of ωB2PLYP, provides accurate excitation energies for conventional systems, as well as correct prescription of negative singlet-triplet gaps for non-conventional systems with inverted gaps, without any necessity for parametric scaling of the same-spin and opposite-spin non-local correlation energies. Examined over "safe" excitations of the QUESTDB set, ωB88PTPSS performs quite well for open-shell systems, correctly and fairly accurately [relative to equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) reference] predicts negative gaps for 50 systems with inverted singlet-triplet gaps, and is one of the leading performers for intramolecular charge-transfer excitations and achieves near-second-order approximate coupled cluster (CC2) and second-order algebraic diagrammatic construction quality for the Q1 and Q2 subsets. Subsequently, we tested ωB88PTPSS on two sets of real-life examples from recent computational chemistry literature-the low energy bands of chlorophyll a (Chl a) and a set of thermally activated delayed fluorescence (TADF) systems. For Chl a, ωB88PTPSS qualitatively and quantitatively achieves DLPNO-STEOM-CCSD-level performance and provides excellent agreement with experiment. For TADF systems, ωB88PTPSS agrees quite well with spin-component-scaled CC2 (SCS-CC2) excitation energies, as well as experimental values, for the gaps between the S1 and T1 excited states.

Adoption of Telemedicine in a Rural US Cancer Center Amid the COVID-19 Pandemic: Qualitative Study.

BACKGROUND: The COVID-19 pandemic necessitated a rapid shift to telemedicine to minimize patient and provider exposure risks. While telemedicine has been used in a variety of primary and specialty care settings for many years, it has been slow to be adopted in oncology care. Health care provider and administrator perspectives on factors affecting telemedicine use in oncology settings are not well understood, and the conditions associated with the COVID-19 pandemic offered the opportunity to study the adoption of telemedicine and the resulting provider and staff perspectives on its use. OBJECTIVE: The aim of this paper is to study the factors that influenced telemedicine uptake and sustained use in outpatient oncology clinics at a US cancer center to inform future telemedicine practices. METHODS: We used purposive sampling to recruit a mix of oncology specialty providers, practice managers, as well as nursing and administrative staff representing 5 outpatient oncology clinics affiliated with the Dartmouth Cancer Center, a large regional cancer center in the northeast of United States, to participate in semistructured interviews conducted over 6 weeks in spring 2021. The interview guide was informed by the 5 domains of the Consolidated Framework for Implementation Research, which include inner and outer setting factors, characteristics of the intervention (ie, telemedicine modality), individual-level factors (eg, provider and patient characteristics), and implementation processes. In total, 11 providers, 3 leaders, and 6 staff participated following verbal consent, and thematic saturation was reached across the full sample. We used a mixed deductive and inductive qualitative analysis approach to study the main influences on telemedicine uptake, implementation, and sustainability during the first year of the COVID-19 pandemic across the 5 settings. RESULTS: The predominant influencers of telemedicine adoption in this study were individual provider experiences and assumptions about patient preference and accessibility. Providers' early telemedicine experiences, especially if negative, influenced preferences for telephone over video and affected sustained use. Telemedicine was most favorably viewed for lower-acuity cancer care, visits less dependent on physical exam, and for patient and caregiver education. A lack of clinical champions, leadership guidance, and vision hindered the implementation of standardized practices and were cited as essential for telemedicine sustainability. Respondents expressed anxiety about sustaining telemedicine use if reimbursements for telephonic visits diminished or ceased. Opportunities to enhance future efforts include a need to provide additional guidance supporting telemedicine use cases and evidence of effectiveness in oncology care and to address provider concerns with communication quality. CONCLUSIONS: In a setting of decentralized care processes, early challenges in telemedicine implementation had an outsized impact on the nature and amount of sustained use. Proactively designed telemedicine care processes with attention to patient needs will be essential to support a sustained role for telemedicine in cancer care.

Factors Influencing Telemedicine Use at a Northern New England Cancer Center During the COVID-19 Pandemic.

PURPOSE: To characterize the use of telemedicine for oncology care over the course of the COVID-19 pandemic in Northern New England with a focus on factors affecting trends. METHODS: We performed a retrospective observational study using patient visit data from electronic health records from hematology-oncology and radiation-oncology service lines spanning the local onset of the pandemic from March 18, 2020, through March 31, 2021. This period was subdivided into four phases designated as lockdown, transition, stabilization, and second wave. Generalized linear mixed regression models were used to estimate the effects of patient characteristics on trends for rates of telemedicine use across phases and the effects of visit type on patient satisfaction and postvisit ER or hospital admissions within 2 weeks. RESULTS: A total of 19,280 patients with 102,349 visits (13.1% audio-only and 1.4% video) were studied. Patient age (increased use in age < 45 and 85 years and older) and urban residence were associated with higher use of telemedicine, especially after initial lockdown. Recent cancer therapy, ER use, and hospital admissions in the past year were all associated with lower telemedicine utilization across pandemic phases. Provider clinical department corresponded to the largest differences in telemedicine use across all phases. ER and hospital admission rates in the 2 weeks after a telehealth visit were lower than those in in-person visits (0.7% v 1.3% and 1.2% v 2.7% for ER and hospital use, respectively; P < .001). Patient satisfaction did not vary across visit types. CONCLUSION: Telemedicine use in oncology during the COVID-19 pandemic varied according to the phase and patient, medical, and health system factors, suggesting opportunities for standardization of care and need for attention to equitable telemedicine access.

Pandemic Use of Telehealth by Oncology at a Rural Academic Medical Center.

Introduction: The COVID-19 pandemic resulted in an exponential increase in telehealth. In response to the pandemic, Dartmouth-Hitchcock Health (D-HH) and its Norris Cotton Cancer Center (NCCC) closed non-essential in-person services on March 17, 2020 and began reopening on April 27, 2020. We examined outpatient telehealth utilization at D-HH and NCCC in the peri-pandemic period and compared utilization to the Academic Medical Center (AMC) overall and to other service lines. Methods: Weekly outpatient volumes, percentage telehealth, percentage video versus audio-only, and percentage of new patients were examined for D-HH, for the AMC, and for selected AMC-based service lines from January 1 to October 31, 2020. Results: Compared with the AMC overall and with five other primarily non-surgical specialties, oncology was lower in the (1) proportion of outpatient visits performed via telehealth (example week 7/12/20: oncology = 11%; AMC = 21%; mean of 5 other specialties = 38%) and (2) percentage of telehealth involving video versus audio-only (7/12/20: oncology = 19%; AMC = 58%; mean of 5 others = 60%). Oncology more closely resembled the surgical specialty of orthopedics (7/12/20: 2% telehealth; 10% of telehealth involved video). Oncology also demonstrated (1) a high proportion of outpatient visits involving procedures (oncology = 22%; orthopedics = 12%) and (2) no difference between telehealth and in-person visits in terms of the percentage involving new patients. Conclusions: During the peri-pandemic period, our oncology service demonstrated a lower than average incorporation of telehealth overall into their outpatient practice and a lower proportion of telehealth performed by video. Further understanding these results and the drivers behind them will be integral for redesigning outpatient oncology care with optimal integration of telehealth.

Willingness to pay for a telemedicine-delivered healthy lifestyle programme.

INTRODUCTION: Effective weight-management interventions require frequent interactions with specialised multidisciplinary teams of medical, nutritional and behavioural experts to enact behavioural change. However, barriers that exist in rural areas, such as transportation and a lack of specialised services, can prevent patients from receiving quality care. METHODS: We recruited patients from the Dartmouth-Hitchcock Weight & Wellness Center into a single-arm, non-randomised study of a remotely delivered 16-week evidence-based healthy lifestyle programme. Every 4 weeks, participants completed surveys that included their willingness to pay for services like those experienced in the intervention. A two-item Willingness-to-Pay survey was administered to participants asking about their willingness to trade their face-to-face visits for videoconference visits based on commute and copay. RESULTS: Overall, those with a travel duration of 31-45 min had a greater willingness to trade in-person visits for telehealth than any other group. Participants who had a travel duration less than 15 min, 16-30 min and 46-60 min experienced a positive trend in willingness to have telehealth visits until Week 8, where there was a general negative trend in willingness to trade in-person visits for virtual. Participants believed that telemedicine was useful and helpful. CONCLUSIONS: In rural areas where patients travel 30-45 min a telemedicine-delivered, intensive weight-loss intervention may be a well-received and cost-effective way for both patients and the clinical care team to connect.

Outpatient Virtual Visits and the "Right" Amount of Telehealth Going Forward.

Background: An exponential increase in outpatient telehealth visits occurred early in the pandemic period that has been followed by volumes that, although lower than peak numbers, are substantially greater than the pre-pandemic period. This provided an opportunity to assess provider perceptions regarding the right prevalence going forward and key obstacles to achieving it. Methods: A 10-question survey was distributed to all outpatient providers within the Dartmouth-Hitchcock Health System. Domains included practice location, specialty, professional degree, experience with telehealth, satisfaction, perception of the amount of telehealth that could be adequately delivered going forward, role of audio-only, and obstacles. Results: Three hundred thirty-six providers completed the survey representing 51 specialties. The most common response regarding the proportion of outpatient visits that could be delivered by video going forward was 21-50% (n = 104) followed by 6-20% (n = 99) and >50% (n = 71). A minority of respondents chose ≤5% (n = 17). In terms of the fraction of video visits for which phone was equally effective, a similar percentage of respondents felt that it was 1/10 (22%), 1/4 (20%), or 1/2 (26%) of visits. Fewer felt that all (7%) or 3/4 (15%) of visits were equally effective, and 10% felt that it was none. Common obstacles identified were the need for a physical exam, unique aspects of providers' patients, patient preference, and issues regarding technology and internet speed/connectivity. Conclusions: After a period of exponential growth in virtual visits due to the pandemic, outpatient providers within an academic health system felt that a substantial portion of future visits could be delivered by this modality.

Telehealth's New Horizon: Providing Smart Hospital-Level Care in the Home.

During the COVID-19 pandemic, medical providers have expanded telehealth into daily practice, with many medical and behavioral health care visits provided remotely over video or through phone. The telehealth market was already facilitating home health care with increasing levels of sophistication before COVID-19. Among the emerging telehealth practices, telephysical therapy; teleneurology; telemental health; chronic care management of congestive heart failure, chronic obstructive pulmonary disease, diabetes; home hospice; home mechanical ventilation; and home dialysis are some of the most prominent. Home telehealth helps streamline hospital/clinic operations and ensure the safety of health care workers and patients. The authors recommend that we expand home telehealth to a comprehensive delivery of medical care across a distributed network of hospitals and homes, linking patients to health care workers through the Internet of Medical Things using in-home equipment, including smart medical monitoring devices to create a "medical smart home." This expanded telehealth capability will help doctors care for patients flexibly, remotely, and safely as a part of standard operations and during emergencies such as a pandemic. This model of "telehomecare" is already being implemented, as shown herein with examples. The authors envision a future in which providers and hospitals transition medical care delivery to the home just as, during the COVID-19 pandemic, students adapted to distance learning and adults transitioned to remote work from home. Many of our homes in the future may have a "smart medical suite" as well as a "smart home office."

Time-Dependent Density Functional Theory Study of Copper(II) Oxo Active Sites for Methane-to-Methanol Conversion in Zeolites.

Copper-exchanged zeolites are useful materials for step-wise methane-to-methanol conversion (MMC). However, methanol yields on copper-exchanged zeolites are often modest, spurring interest in the development of active-site species that are activated at moderate temperatures, afford greater yields, and provide excellent methanol selectivities. Ultraviolet-visible (UV-vis) spectroscopy is a major tool for characterizing the active-sites and their evolution during the step-wise MMC process. However, computation of the UV-vis spectra of the copper-oxo active sites using Tamm-Dancoff time-dependent density functional theory (TDA-DFT) can be quite problematic. This has led to utilization of expensive methods based on multireference approaches, Green functions, and the Bethe-Salpeter equation. In this work, we examined the optical spectra of [CuO]+, [Cu2O]2+, [Cu2O2]2+, and [Cu3O3]2+ species implicated in MMC in zeolites. For the larger species, we examined how agreement with experimental data is improved with increasingly larger cluster models. For [CuO]+, we compared TDA-DFT against restricted active space 2nd-order perturbation theory, RASPT2. We found that signature peaks for [CuO]+ have multireference behavior. The excited states have many configuration state functions with a double excitation character. These effects are likely responsible for the poor utility of conventional TDA-DFT methods. Indeed, we obtain good agreement with experimental data and RASPT2 after accounting for 2h/2p excitations within TDA-DFT with a previously described configuration interaction singles and doubles, CIS(D)-style scheme. This was the case for [CuO]+, [Cu2O]2+, as well as a [Cu2O2]2+ species. Using a long-range corrected double-hybrid, ωB2PLYP, we provide for the first time computational evidence for the experimental UV-vis spectrum of the [Cu3O3]2+ active site motif.

Diabetic Gait Is Not Just Slow Gait: Gait Compensations in Diabetic Neuropathy.

BACKGROUND: Neuropathic complications from diabetes mellitus affect multiple nerve types and may manifest in gait. However, gait compensations are still poorly understood, as narrow analyses and lack of speed controls have contributed to conflicting or equivocal results. PURPOSE: To evaluate gait mechanics and energetics in diabetic peripheral polyneuropathy. METHODS: Instrumented gait analysis was performed on 14 participants with diabetic peripheral polyneuropathy and 14 matched controls, walking at 1.0 m/s. A full-body model with a multisegment foot was used to calculate inverse dynamics and analyze sagittal plane metrics and time series waveforms across stance phase. RESULTS: Alterations included increased hip and knee flexion in early stance followed by a prolonged hip extension moment in midstance. Late stance ankle dorsiflexion and power absorption were increased, and final push-off was delayed and truncated. CONCLUSION: A neuropathic diabetic gait shares important similarities to a mild crouch gait with weakness/dysfunction in the foot and ankle. This study highlights two main compensation mechanisms that have been overlooked in previous literature. First, increased triceps surae stretch in terminal stance may be used to increase proprioception and/or energy storage, while a prolonged hip extension moment in midstance compensates for a limited push-off. These result in an overall workload shift from distal to proximal joints. Clinical assessment, monitoring, and treatment of neuropathy may benefit by focusing on these specific functional alterations.

Feasibility and acceptability of a rural, pragmatic, telemedicine-delivered healthy lifestyle programme.

BACKGROUND: The public health crisis of obesity leads to increasing morbidity that are even more profound in certain populations such as rural adults. Live, two-way video-conferencing is a modality that can potentially surmount geographic barriers and staffing shortages. METHODS: Patients from the Dartmouth-Hitchcock Weight and Wellness Center were recruited into a pragmatic, single-arm, nonrandomized study of a remotely delivered 16-week evidence-based healthy lifestyle programme. Patients were provided hardware and appropriate software allowing for remote participation in all sessions, outside of the clinic setting. Our primary outcomes were feasibility and acceptability of the telemedicine intervention, as well as potential effectiveness on anthropometric and functional measures. RESULTS: Of 62 participants approached, we enrolled 37, of which 27 completed at least 75% of the 16-week programme sessions (27% attrition). Mean age was 46.9 ± 11.6 years (88.9% female), with a mean body mass index of 41.3 ± 7.1 kg/m2 and mean waist circumference of 120.7 ± 16.8 cm. Mean patient participant satisfaction regarding the telemedicine approach was favourable (4.48 ± 0.58 on 1-5 Likert scale-low to high) and 67.6/75 on standardized questionnaire. Mean weight loss at 16 weeks was 2.22 ± 3.18 kg representing a 2.1% change (P < .001), with a loss in waist circumference of 3.4% (P = .001). Fat mass and visceral fat were significantly lower at 16 weeks (2.9% and 12.5%; both P < .05), with marginal improvement in appendicular skeletal muscle mass (1.7%). In the 30-second sit-to-stand test, a mean improvement of 2.46 stands (P = .005) was observed. CONCLUSION: A telemedicine-delivered, intensive weight loss intervention is feasible, acceptable, and potentially effective in rural adults seeking weight loss.

Decreased STAT3 Phosphorylation Mediates Cell Swelling in Ammonia-Treated Astrocyte Cultures.

Brain edema, due largely to astrocyte swelling, and the subsequent increase in intracranial pressure and brain herniation, are major complications of acute liver failure (ALF). Elevated level of brain ammonia has been strongly implicated in the development of astrocyte swelling associated with ALF. The means by which ammonia brings about astrocyte swelling, however, is incompletely understood. Recently, oxidative/nitrosative stress and associated signaling events, including activation of mitogen-activated protein kinases (MAPKs), as well as activation of the transcription factor, nuclear factor-kappaB (NF-κB), have been implicated in the mechanism of ammonia-induced astrocyte swelling. Since these signaling events are known to be regulated by the transcription factor, signal transducer and activator of transcription 3 (STAT3), we examined the state of STAT3 activation in ammonia-treated cultured astrocytes, and determined whether altered STAT3 activation and/or protein expression contribute to the ammonia-induced astrocyte swelling. STAT3 was found to be dephosphorylated (inactivated) at Tyrosine705 in ammonia-treated cultured astrocytes. Total STAT3 protein level was also reduced in ammonia-treated astrocytes. We also found a significant increase in protein tyrosine phosphatase receptor type-1 (PTPRT-1) protein expression in ammonia-treated cultured astrocytes, and that inhibition of PTPRT-1 enhanced the phosphorylation of STAT3 after ammonia treatment. Additionally, exposure of cultured astrocytes to inhibitors of protein tyrosine phosphatases diminished the ammonia-induced cell swelling, while cultured astrocytes over-expressing STAT3 showed a reduction in the astrocyte swelling induced by ammonia. Collectively, these studies strongly suggest that inactivation of STAT3 represents a critical event in the mechanism of the astrocyte swelling associated with acute liver failure.

Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells.

Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and ß-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells.

Opioid-related Policies in New England Emergency Departments.

OBJECTIVES: The opioid abuse and overdose epidemic in the United States has led to the need for new practice policies to guide clinicians. We describe implementation of opioid-related policies in emergency departments (EDs) in New England to gauge progress and determine where further work is needed. METHODS: This study analyzed data from the 2015 National Emergency Department Inventory-New England survey. The survey queried directors of every ED (n = 195) in the six New England states to determine the implementation of five specific policies related to opioid management. ED characteristics (e.g., annual visits, location, and admission rates) were also obtained and a multivariable analysis was conducted to identify ED characteristics independently associated with the number of opioid-related policies implemented. RESULTS: Overall, 169 EDs (87%) responded, with a >80% response rate in each state. Implementation of opioid-related policies varied as follows: 1) use of a screening tool for patients with suspected prescription opioid abuse potential (n = 30, 18%), 2) access state prescription drug monitoring program (PDMP) before prescribing opioids (n = 132, 78%), 3) notify the primary opioid prescriber when prescribing opioids for ED patients with chronic pain (n = 69, 41%), 4) refer patients with opioid abuse to recovery resources (n = 117, 70%), and 5) prescribe naloxone to patients at risk of opioid overdose after ED discharge (n = 19, 12%). EDs located in metropolitan areas and with at least one attending physician on duty 24/7 were less likely to implement opioid policies (incident rate ratio [IRR] = 0.65, 95% confidence interval [CI] = 0.48-0.89; and IRR = 0.78, 95% CI = 0.6-1.0, respectively) while EDs with ≥15% hospitalization rate that used electronic computerized medication ordering and those in Rhode Island were more likely to implement opioid policies (IRR = 1.23, 95% CI = 1.03-1.48; IRR = 1.95, 95% CI = 1.19-3.22; and IRR = 1.30, 95% CI = 1.08-1.56, respectively). CONCLUSIONS: The implementation of opioid-related policies varies among New England EDs. The presence of policies recommending use of screening tools and prescribing naloxone for at-risk patients was low, whereas those regarding utilization of the PDMP and referral of patients with opioid abuse to recovery resources were more common. These data provide important benchmarks for future evaluations and recommendations.

Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair.

INTRODUCTION: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair. AREAS COVERED: This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body. EXPERT OPINION: Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non-union fractures.

TAp63γ and ΔNp63ß promote osteoblastic differentiation of human mesenchymal stem cells: regulation by vitamin D3 Metabolites.

The transcription factor p63 is required for skeletal formation, and is important for the regulation of 1α,25(OH)2D3 receptor (VDR) in human mesenchymal stem cells (hMSC). Herein we report that TAp63γ and ΔNp63ß appear to be an integral part of the osteoblastic differentiation of hMSC and are differentially regulated by the vitamin D3 metabolites 1α,25(OH)2D3 and 24R,25(OH)2D3. We compared the endogenous expression of p63 isoforms (TA- and ΔNp63) and splice variants (p63α, -ß, -γ), in naive hMSC and during osteoblastic differentiation of hMSC. TAp63α and -ß were the predominant p63 variants in naive, proliferating hMSC. In contrast, under osteoblastic differentiation conditions, expression of p63 changed from the TAp63α and -ß to the TAp63γ and ΔNp63ß variants. Transient overexpression of the p63 variants demonstrated that TAp63ß, ΔNp63ß, and ΔNp63γ increased alkaline phosphatase activity and ΔNp63α and -γ increased the expression of mRNA for osteocalcin and osterix. Our results support the hypothesis that TAp63α and -ß promote a naive state in hMSC. Moreover, TAp63γ is increased during and promotes early osteoblastic differentiation through the expression of pro-osteogenic genes; VDR, Osterix, Runx2 and Osteopontin. ΔNp63ß also appears to support osteogenic maturation through increased alkaline phosphatase activity. Treatment with 1α,25(OH)2D3 increased the expression of mRNA for ΔNp63, while addition of 24R,25(OH)2D3 increased the expression of TA- and ΔNp63γ variants. These novel findings demonstrate for the first time that p63 variants are differentially expressed in naive hMSC (TAp63α,ß), are important during the osteoblastic differentiation of hMSC (TAp63γ and ΔNp63ß), and are differentially regulated by the vitamin D3 metabolites, 1α,25(OH)2D3 and 24R,25(OH)2D3. The molecular nuances and mechanisms of osteoblastic differentiation presented here will hopefully improve our understanding of bone development, complications in bone repair (mal- and non-union fractures), osteoporosis and possibly lead to new modalities of treatment.

The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage.

The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis.

Characteristics and Patterns of Metastatic Disease from Chordoma.

Chordoma is a rare, slow-growing malignant tumor arising from notochordal remnants. A retrospective review of patient records at two major referral centers was undertaken to assess the incidence, location, and prognostic factors of metastatic disease from chordoma. 219 patients with chordoma (1962-2009) were identified. 39 patients (17.8%) developed metastatic disease, most frequently to lung (>50%). Median survival from the time of initial diagnosis was 130.4 months for patients who developed metastatic disease and 159.3 months for those who did not (P = 0.05). Metastatic disease was most common in the youngest patients (P = 0.07), and it was 2.5 times more frequent among patients with local recurrence (26.3%) than in those without (10.8%) (P = 0.003). Patient survival with metastatic disease was highly variable, and it was dependent on both the location of the tumor primary and the site of metastasis. Metastasis to distal bone was the most rapid to develop and had the worst prognosis.