Transitional care from skilled nursing facilities to home: study protocol for a stepped wedge cluster randomized trial.

BACKGROUND: Skilled nursing facility (SNF) patients are medically complex with multiple, advanced chronic conditions. They are dependent on caregivers and have experienced recent acute illnesses. Among SNF patients, the rate of mortality or acute care use is over 50% within 90 days of discharge, yet these patients and their caregivers often do not receive the quality of transitional care that prepares them to manage serious illnesses at home. METHODS: The study will test the efficacy of Connect-Home, a successfully piloted transitional care intervention targeting seriously ill SNF patients discharged to home and their caregivers. The study setting will be SNFs in North Carolina, USA, and, following discharge, in patients' home. Using a stepped wedge cluster randomized trial design, six SNFs will transition at randomly assigned intervals from standard discharge planning to the Connect-Home intervention. The SNFs will contribute data for patients (N = 360) and their caregivers (N = 360), during both the standard discharge planning and Connect-Home time periods. Connect-Home is a two-step intervention: (a) SNF staff create an individualized Transition Plan of Care to manage the patient's illness at home; and (b) a Connect-Home Activation RN visits the patient's home to implement the written Transition Plan of Care. A key feature of the trial includes training of the SNF and Home Care Agency staff to complete the transition plan rather than using study interventionists. The primary outcomes will be patient preparedness for discharge and caregiver preparedness for caregiving role. With the proposed sample and using a two-sided test at the 5% significance level, we have 80% power to detect a 18% increase in the patient's preparedness for discharge score. We will employ linear mixed models to compare observations between intervention and usual care periods to assess primary outcomes. Secondary outcomes include (a) patients' quality of life, functional status, and days of acute care use and (b) caregivers' burden and distress. DISCUSSION: Study results will determine the efficacy of an intervention using existing clinical staff to (a) improve transitional care for seriously ill SNF patients and their caregivers, (b) prevent avoidable days of acute care use in a population with persistent risks from chronic conditions, and (c) advance the science of transitional care within end-of-life and palliative care trajectories of SNF patients and their caregivers. While this study protocol was being implemented, the COVID-19 pandemic occurred and this protocol was revised to mitigate COVID-related risks of patients, their caregivers, SNF staff, and the study team. Thus, this paper includes additional material describing these modifications. TRIAL REGISTRATION: ClinicalTrials.gov NCT03810534 . Registered on January 18, 2019.

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.

The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5.

Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5, we made an inducible Elf5 short hairpin-RNA knock-down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin induction of Elf5 expression tempered the antiproliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.

Tolerability of high-dose topical tretinoin: the Veterans Affairs Topical Tretinoin Chemoprevention Trial.

BACKGROUND: Topical tretinoin is a medication commonly used for acne that has potential application in the long-term treatment of photodamaged skin. However, there are few published data regarding the tolerability of high-dose tretinoin with long-term use. OBJECTIVES: To assess the long-term tolerability of tretinoin 0.1% cream. METHODS: A randomized, multicentre, double-blind, controlled trial for chemoprevention of keratinocyte carcinomas (i.e. basal cell or squamous cell carcinomas) using topical tretinoin cream to the face and ears was conducted. All participants were veterans and had a history of two or more keratinocyte carcinomas over the previous 5 years. Participants were examined (by a study dermatologist) and interviewed every 6 months (for up to 5.5 years to May 2004). Treatment comprised tretinoin 0.1% cream or vehicle control cream once daily, then twice daily as tolerated. Participants were instructed to step down application frequency to once daily or less if twice daily was not tolerated. The main outcome measures were reported side-effects, frequency of cream application and attendance at study visits. Appropriate data were available for four of the six clinical sites of this trial. RESULTS: Data from 736 randomized participants (mean age 71 years; 97% men) from four clinical sites were analysed. The tretinoin group more commonly reported one or more side-effects at the 6-month follow-up than the control group (61% vs. 42%, P < 0.0001). Side-effects decreased over time in both groups, but to a greater extent in the tretinoin group, and the difference became nonsignificant at 30 months. Burning was the most common side-effect (39% tretinoin vs. 17% control, P < 0.0001). There was no difference in severity of side-effects among those affected. Of the participants who reported burning in either group, most reported mild burning; only 11% of those with burning in the tretinoin group reported it as severe (mild 62% tretinoin vs. 70% placebo; severe 11% vs. 5%; P = 0.4). Itching (24% vs. 16%, P = 0.01) and other local cutaneous reactions (12% vs. 6%, P = 0.01) were also more commonly reported by the tretinoin group at 6 months. There was no difference in numbness (2% vs. 2%, P = 0.9). Participants in the tretinoin group were less likely to apply cream twice daily at 6 months (29% vs. 43%, P = 0.0002). This difference persisted over the entire duration of follow-up. There was little difference between groups in attendance at study visits or completion of telephone interviews (92% vs. 95%, P = 0.06). No unexpected adverse events were reported. CONCLUSIONS: Overall, the tolerability level of topical tretinoin was high in this study population, with almost 40% of the tretinoin group reporting no side-effects, and the majority (67%) tolerating at least once-daily dosing at 6-month follow-up. High-dose topical tretinoin is feasible for long-term use in this population.

Identifying the high-risk patient with clinically relevant embolisation after carotid endarterectomy.

OBJECTIVES: Sustained embolisation after carotid endarterectomy (CEA) predicts an increased risk of stroke due to post-operative carotid thrombosis (POCT). Progression towards stroke can be prevented by transcranial Doppler (TCD) directed intravenous Dextran therapy. However, TCD monitoring is extremely labour intensive. The aim of this study was to see whether a small cohort of high-risk patients could be identified following a 30-min period of monitoring in the Recovery Area of the operating theatre so as to reduce the overall burden of monitoring for the majority of patients. METHODS: Retrospective audit of prospectively acquired data in 821 patients with an accessible temporal window who had undergone 3h of TCD monitoring after CEA. Patients with >25 emboli in any 10 min period or large emboli distorting the waveform received Dextran. RESULTS: Group 1: 694 patients (85%) with

Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU.

Hypothermia has been shown to be neuroprotective in some newborns with moderate-to-severe perinatal hypoxic-ischemic encephalopathy (HIE). In 2006, the American Academy of Pediatrics recommended that institutions that choose to use therapeutic hypothermia do so in the context of a rigorous protocol, with systematic collection of patient data including neurodevelopmental follow-up. In this report, we describe our experience with implementation of a 'Hypothermia for HIE' program in a single tertiary care Neonatal Intensive Care Unit (NICU). Important components of the program include detailed protocols, staff and outreach education, early initiation of cooling in both inborn and outborn patients, maintaining stable hypothermia during neonatal transport, and comprehensive neurologic evaluation including serial EEGs, brain MRI and neurodevelopmental follow-up. In the first 2 years of the program, we have used hypothermia therapy in 21 patients, 18 with perinatal and 3 with early postnatal events leading to HIE. Eleven of fifteen outborn patients were cooled prior to and during transport, resulting in initiation of therapy 3 h sooner than if therapy had been delayed until arrival at our center. While lowering the body temperature of encephalopathic newborns is not difficult, addressing the complex medical problems of this vulnerable group of patients requires an experienced multidisciplinary team in regional referral centers.

Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres.

An adequate and appropriate response to physiological and pathophysiological stresses is critical for long-term homeostasis and viability of the aging organism. Previous work has pointed to the immune system, telomeres and DNA repair pathways as important and distinct determinants of a normal healthy lifespan. In this study, we explored the genetic interactions of telomeres and DNA-PKcs, a protein involved in non-homologous end-joining (NHEJ) and immune responses, in the context of a key aspect of aging and lifespan--the capacity to mount an acute and appropriate immune-mediated stress response. We observed that the combination of DNA-PKcs deficiency and telomere dysfunction resulted in a shortened lifespan that was reduced further following viral infection or experimental activation of the innate immune response. Analysis of the innate immune response in the DNA-PKcs-deficient mice with short dysfunctional telomeres revealed high basal serum levels of tumor necrosis factor alpha (TNFalpha) and hyper-active cytokine responses upon challenge with polyinosinic-polycytidylic acid (poly-IC). We further show that serum cytokine levels become elevated in telomere dysfunctional mice as a function of age. These results raise speculation that these genetic factors may contribute to misdirected immune responses of the aged under conditions of acute and chronic stress.

In situ photoimmunotherapy: a tumour-directed treatment for melanoma.

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

Duplex ultrasound scanning is reliable in the detection of endoleak following endovascular aneurysm repair.

OBJECTIVE: To investigate the value of duplex ultrasound scanning (DUSS) in the routine follow up of patients following EVAR. METHODS: Imaging was reviewed for 310 consecutive patients undergoing EVAR at a single centre. Concurrent ultrasound and CT scans were defined as having occurred within 6 months of each other. There were 244 paired concurrent DUSS and CT scans which were used for further analysis. These modalities were compared with respect to sensitivity, specificity, positive and negative predictive values and level of agreement (by Kappa statistics) using CT as the 'gold standard'. RESULTS: DUSS failed to detect a number of endoleaks which were seen on CT and the sensitivity of this test was therefore poor (67%). However, the specificity of DUSS compared more favourably with a value of 91%. Positive predictive values ranged from 33-100% but negative predictive values were more reliable with values of 91-100% at all time points post operatively. There were no type I leaks, or endoleaks requiring intervention which were missed on DUSS. Overall, there was a 'fair' level of agreement between the two imaging modalities using Kappa statistics. CONCLUSION: Although DUSS is not as sensitive as CT scanning in the detection of endoleak, no leaks requiring intervention were missed on DUSS in this study. DUSS is much cheaper than CT and avoids high doses of radiation. DUSS therefore remains a valuable method of follow up after EVAR and can reduce the need for repeated CT scans.

The complete genome sequence, organization and affinities of carrot red leaf virus.

A sequence of 5723 nucleotides (GenBank accession number: AY695933) is reported for the RNA genome of an isolate of Carrot red leaf virus (CtRLV). The sequence is predicted to contain six large open reading frames and non coding sequences of 28 nucleotides at the 5' end, 110 nucleotides at the 3' end, and 215 nucleotides between the two main blocks of coding sequences. The 5' coding region encodes two polypeptides with calculated molecular masses (Mr) of 28.6 kDa (P0) and 68.2 kDa (P1) that overlap in different reading frames. Circumstantially, the third ORF in the 5' block is putatively translated by frameshift read-through to yield a polypeptide (P1 + P2) with a calculated Mr of 116.9 kDa. Frameshifting is predicted at a "shifty" sequence (GGGAAAC; nt 1523-1529) also found in most members of the genus Polerovirus. The C-terminal region of the 116.9 kDa polypeptide includes the consensus sequence for the viral RNA-directed RNA polymerase. The 3' block of coding sequence defines three putative polypeptides of: 23.0 kDa (P3), 21.3 kDa (P4, in a different reading frame) and 77.2 kDa (P3 + P5, by read-through of P3) respectively. From the genome structure of CtRLV, it is suggested that this virus belongs to the genus Polerovirus, rather than either the genus Luteovirus or the genus Enamovirus.

Heterogeneity in codon usages of sobemovirus genes.

When conventional phylogenetic trees were built using 14 genome sequences of 9 sobemoviruses, two main lineages were apparent: monocot-infecting viruses and dicot-infecting viruses. To investigate whether members of the genus Sobemovirus originated from monocot hosts or from dicot hosts, we constructed relationship trees based on Relative Synonymous Codon Usage (RSCU) of the viruses. The RSCU relationship trees grouped the monocot-infecting and dicot-infecting viruses even better than the genome phylogenetic trees. The RSCU approach also enabled direct comparisons among viral and host species. When host species were added into the RSCU tree, the viral species clustered with the monocot hosts, indicating codon usage homologies to monocots. The stability of the RSCU tree was improved when RSCU values were calculated for individual viral open reading frames (ORFs). Most interestingly, the codon usages of the viral ORF-2 that encodes the replicase showed affinity to that of the plants whereas codon usages of the other viral ORFs were not relevant to the host species. All ORF-2s from 3 monocot viruses and 4 out of 6 dicot viruses had greater RSCU affinities to sequences of ORFs in monocot than to dicot hosts, possibly indicating that ORF-2, and therefore the replicase module of sobemovirus has a monocot origin.

Faraday tilting of water-immersed granular beds.

Under low-frequency vertical vibration, a system of fine grains within a fluid is observed to tilt or to form piles, an effect studied by Faraday for grains in air. Here, we investigate the physical mechanisms behind Faraday tilting in a bed of vertically vibrated bronze spheres fully immersed in water. Experimental observations of surface tilting and bulk convection are compared with the results of molecular dynamics simulations in which the water is treated as an incompressible fluid. Our simulations reproduce the main features observed experimentally. Most tilt construction is shown to be due to horizontal fluid flow within the bed, principally occurring when the gap between the bed and the supporting platform is close to a maximum. Tilt destruction occurs by granular surface flow and in the bulk of the bed at times during each vibratory cycle close to and just later than bed impact. Destruction becomes more important for higher values of frequency and vibration amplitude, leading to lower tilt angles, partial tilting, or the symmetric domed geometry of Muchowski flow.

Construction and properties of a gene-silencing vector based on Poplar mosaic virus (genus Carlavirus).

A gene-silencing vector based on a full-length genomic clone of Poplar mosaic virus (PopMV) was constructed, with coat protein and movement protein genes removed, and containing instead, the coding sequence for green fluorescent protein (GFP). This paper demonstrates that the PopMV-derived gene-silencing vector was able to silence GFP expression in GFP transgenic Nicotiana benthamiana plants. The full-length genome of an Oxford isolate of PopMV (PV275) was cloned and sequenced. A full-length PopMV clone, under transcriptional control of the 35SCaMV promoter was then constructed, and the clone was able to replicate locally in Nicotiana species. Several autonomous plant RNA and DNA viruses have been converted into vectors and implemented for virus-induced gene-silencing (VIGS) of transgenes and endogenous genes [Burton, R., Gibeaut, D., Bacic, A., Findlay, K., Roberts, K., Hamilton, A., Baulcombe, D., Fincher, G., 2000. Virus-induced silencing of a plant cellulose synthase gene. Plant Cell 12, 691-706; Dalmay, T., Horsefield, R., Braunstein, T.H., Baulcombe, D.C., 2001. SDE3 encodes an RNA helicase required for post-transcriptional gene silencing in Arabidopsis. EMBO J. 20, 2069-2077; Gossele, V., Fache, I., Meulewaeter, F., Cornelissen, M., Metzlaff, M., 2002. SVISS--a novel transient gene silencing system for gene function discovery and validation in tobacco plants. Plant J. 32, 859-866; Holzberg, S., Brosio, P., Gross, C., Pogue, G.P., 2002. Barley stripe mosaic virus-induced gene silencing in a monocot plant. Plant J. 30, 315-327; Ratcliff, F., Martin-Hernandez, A., Baulcombe, D., 2000. Tobacco rattle virus as a vector for analysis of gene function by silencing. Plant J. 25, 237-245; Ruiz, M., Vionnet, O., Baulcombe, D., 1998. Initiation and maintenance of virus-induced gene silencing. Plant Cell 10, 937-946]. The use of a virus that naturally infects trees as a gene-silencing vector has not been demonstrated before. The ability to systemically silence a plant transgene following the production of a gene-silencing signal from a locally replicating viral-construct derived from a carlavirus has not to our knowledge been shown before.

Treatment of lentigo maligna with topical imiquimod.

A published case report and anecdotal experience suggested that topical imiquimod is an effective treatment for stage 0 melanoma (lentigo maligna). To gauge the efficacy of this therapy, we undertook a trial of topical imiquimod in 30 subjects with histologically confirmed lentigo maligna. Thirty subjects with lentigo maligna were recruited for an open-labelled efficacy trial with daily topical application of imiquimod 5% cream for 3 months. Study subjects were enrolled from the Dermatology service of the University of Oklahoma, the Oklahoma City Veteran's Administration Hospital Dermatology service and from referrals for the study from other practitioners. In order to determine an initial response rate, a four-quadrant biopsy was carried out on all patients 1 month after cessation of treatment, targeting the most clinically and dermatoscopically suspicious areas. Of 28 evaluable subjects who have completed the 3-month treatment phase, 26 (93%) were complete responders and two were treatment failures at the time of the 4-quadrant biopsy. Over 80% of the 28 subjects that completed treatment have been followed for more than 1 year with no relapses. The results of this study demonstrate that topical imiquimod produces a high complete response rate in lentigo maligna when applied daily for 3 months.

Air-driven Brazil nut effect.

A large heavy object may rise to the top of a bed of smaller particles under the influence of vertical vibration, the "Brazil nut effect." Recently it has been noted that interstitial air can influence the Brazil nut rise time. Here we report that the air movement induced by vertical vibration produces a very strong Brazil nut effect for fine granular beds. We use a porous-bottomed box to investigate the mechanism responsible for this effect and to demonstrate that it is related to the piling of fine beds, first reported by Chladni and studied by Faraday. Both effects are due to the strong interaction of the fine particles with the air, as it is forced through the bed by the vibration.

Chaotic dynamics of an air-damped bouncing ball.

A ball bouncing elastically upon a vertically vibrated platform is one of the simplest examples of a chaotic system. If dissipation is introduced at each bounce through a coefficient of restitution, the motion is no longer chaotic; the trajectories exhibit locking solutions that result in periodic behavior. Here we investigate the dynamics of a bouncing ball influenced by air damping. We consider the effects of both static air and air moving with the platform, and show that there is an exact mapping between them. In either case, the system has a rather complex dynamical behavior including truly chaotic trajectories. Our results highlight the importance of air effects for fine particulate systems.

Reliability of counting actinic keratoses before and after brief consensus discussion: the VA topical tretinoin chemoprevention (VATTC) trial.

OBJECTIVE: To assess the reliability of counts of actinic keratoses (AKs) and the effect of a brief joint discussion of discrepancies on that reliability. DESIGN AND INTERVENTION: Seven dermatologists independently counted AKs on the face and ears before and after a brief joint discussion of discrepancies. SETTING AND PATIENTS: A volunteer sample of 9 patients from the ongoing VA (Department of Veterans Affairs) Topical Tretinoin Chemoprevention (VATTC) Trial. All participating individuals are veterans and have had 2 or more keratinocyte carcinomas (basal or squamous cell carcinoma) in the 5 years before enrollment in the study. MAIN OUTCOME MEASURE: Standard deviation of estimates of the Poisson regression parameter for the dermatologists. RESULTS: Substantial variation was found among the dermatologists in their AK counts. The SD of the parameter estimates for the dermatologists decreased from 0.45 to 0.24 after the brief joint discussion, a 47% decrease (P =.076). The variation attributable to the dermatologists also decreased substantially (chi(2)(6) decrease, 94 to 12). CONCLUSIONS: Actinic keratoses are common, and there is a continuous spectrum of lesions that ranges from sun-damaged skin to squamous cell carcinoma in situ. Clinical distinguishing features may be difficult to delineate precisely. Counts of AK are commonly performed, but appear to be unreliable, even when performed by experienced dermatologists. Joint discussion of discrepancies may enhance the reliability of these counts, although substantial variation remains. Research that relied on these counts must be reevaluated in light of the marked variation among expert observers. Future studies should consider measures to assess and enhance reliability.