Telehealth and Telemedicine: Regulatory and Medicolegal Landscape.

ABSTRACT: Telehealth and telemedicine experienced remarkable growth during and after the recent COVID-19 pandemic. Telehealth is generally defined as nonclinical services that employ telecommunication technology. Telemedicine refers more specifically to remote clinical services including diagnosis, monitoring, and treatment. Nuclear medicine is no exception in employing telemedicine increasingly in clinical practice for image interpretation and treatment consultation and care delivery supervision. There is no doubt that soon, the use of tele-nuclear medicine will increase, comparable to the employment of telecommunication in other fields of medicine. We review the medicolegal and regulatory aspects of the evolution in the clinical practice of medicine through telehealth and telemedicine.

Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo.

HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5'exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery.

Estimated Healthcare Costs of Melanoma and Keratinocyte Skin Cancers in Australia and Aotearoa New Zealand in 2021.

Australia and Aotearoa New Zealand have the highest incidence of melanoma and KC in the world. We undertook a cost-of-illness analysis using Markov decision-analytic models separately for melanoma and keratinocyte skin cancer (KC) for each country. Using clinical pathways, the probabilities and unit costs of each health service and medicine for skin cancer management were applied. We estimated mean costs and 95% uncertainty intervals (95% UI) using Monte Carlo simulation. In Australia, the mean first-year costs of melanoma per patient ranged from AU$644 (95%UI: $642, $647) for melanoma in situ to AU$100,725 (95%UI: $84,288, $119,070) for unresectable stage III/IV disease. Australian-wide direct costs to the Government for newly diagnosed patients with melanoma were AU$397.9 m and AU$426.2 m for KCs, a total of AU$824.0 m. The mean costs per patient for melanoma ranged from NZ$1450 (95%UI: $1445, $1456) for melanoma in situ to NZ$77,828 (95%UI $62,525, $94,718) for unresectable stage III/IV disease. The estimated total cost to New Zealand in 2021 for new patients with melanoma was NZ$51.2 m, and for KCs, was NZ$129.4 m, with a total combined cost of NZ$180.5 m. These up-to-date national healthcare costs of melanoma and KC in Australia and New Zealand accentuate the savings potential of successful prevention strategies for skin cancer.

The CCCTC Binding Factor, CTRL2, Modulates Heterochromatin Deposition and the Establishment of Herpes Simplex Virus 1 Latency In Vivo.

The cellular insulator protein CTCF plays a role in herpes simplex virus 1 (HSV-1) latency through the establishment and regulation of chromatin boundaries. We previously found that the CTRL2 regulatory element downstream from the latency-associated transcript (LAT) enhancer was bound by CTCF during latency and underwent CTCF eviction at early times postreactivation in mice latently infected with 17syn+ virus. We also showed that CTRL2 was a functional enhancer-blocking insulator in both epithelial and neuronal cell lines. We hypothesized that CTRL2 played a direct role in silencing lytic gene expression during the establishment of HSV-1 latency. To test this hypothesis, we used a recombinant virus with a 135-bp deletion spanning only the core CTRL2 insulator domain (ΔCTRL2) in the 17syn+ background. Deletion of CTRL2 resulted in restricted viral replication in epithelial cells but not neuronal cells. Following ocular infection, mouse survival decreased in the ΔCTRL2-infected cohort, and we found a significant decrease in the number of viral genomes in mouse trigeminal ganglia (TG) infected with ΔCTRL2, indicating that the CTRL2 insulator was required for the efficient establishment of latency. Immediate early (IE) gene expression significantly increased in the number of ganglia infected with ΔCTRL2 by 31 days postinfection relative to the level with 17syn+ infection, indicating that deletion of the CTRL2 insulator disrupted the organization of chromatin domains during HSV-1 latency. Finally, chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) analyses of TG from ΔCTRL2-infected mice confirmed that the distribution of the repressive H3K27me3 (histone H3 trimethylated at K27) mark on the ΔCTRL2 recombinant genomes was altered compared to that of the wild type, indicating that the CTRL2 site modulates the repression of IE genes during latency.IMPORTANCE It is becoming increasingly clear that chromatin insulators play a key role in the transcriptional control of DNA viruses. The gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) utilize chromatin insulators to order protein recruitment and dictate the formation of three-dimensional DNA loops that spatially control transcription and latency. The contribution of chromatin insulators in alphaherpesvirus transcriptional control is less well understood. The work presented here begins to bridge that gap in knowledge by showing how one insulator site in HSV-1 modulates lytic gene transcription and heterochromatin deposition as the HSV-1 genome establishes latency.

Comparison of PTCH1, COX-2, p53, and Ki-67 protein expression in basal cell carcinomas of nodular and superficial subtypes arising on the head and trunk.

BACKGROUND: There is some evidence that basal cell carcinomas (BCCs) arising on different anatomic sites and developing to different histological subtypes differ in their pathophysiology. The expression of a number of proteins, including PTCH1, COX-2, p53, and Ki-67, is frequently altered in BCC development. OBJECTIVES: This study sought to determine whether protein expression differs between BCCs at different anatomic sites and of different histological subtypes. METHODS: Expression of PTCH1, COX-2, p53, and Ki-67 proteins was compared between: (i) BCCs arising on the head (n = 55) and trunk (n = 53), and (ii) nodular (n = 52) and superficial (n = 43) BCCs. The intensity of immunohistochemistry (IHC) staining (low, moderate, strong, very strong) for PTCH1 and COX-2 proteins was measured and the proportions of p53- and Ki-67-positive cells quantified. RESULTS: The proportion of cells expressing Ki-67 was higher in tumor tissue than in non-malignant epidermis, whereas the opposite was found for PTCH1. The IHC staining intensity for PTCH1 was substantially greater in truncal BCCs than in BCCs on the head (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.63-8.96). The intensity of staining for PTCH1 was greater for superficial than for nodular BCCs (OR 3.70, 95% CI 1.53-8.97), and superficial BCCs showed a higher proportion of Ki-67-positive cells (OR 5.57, 95% CI 1.66-18.67). CONCLUSIONS: These differences suggest that the pathophysiology of BCC differs between lesions on the head and trunk and between nodular and superficial subtypes, perhaps indicating differences in their etiology.

Basal cell carcinomas on sun-protected vs. sun-exposed body sites: a comparison of phenotypic and environmental risk factors.

BACKGROUND: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in White populations. There are indications that risk factors for BCC may differ according to the anatomic site of the tumour but this is not well understood. PURPOSE: To compare phenotypic and environmental risk factors for BCCs arising on sun-protected sites with that of those on sun-exposed sites. METHODS: We conducted a case-case study in which people who had been diagnosed with incident BCC were recruited between February 2012 and September 2013 in Brisbane, Australia. RESULTS: Fair skin (OR: 4.50; 95% CI: 1.22, 16.59), having more than 15 lesions frozen/burnt off compared to less than 5 (OR: 5.68; 95% CI: 1.78, 18.08) and severe acne (OR: 5.25; 95% CI: 1.34, 20.56) were associated with increased risk of BCC on sun-protected sites. The presence of more than 5 nevi on the body was associated with decreased risk (OR: 0.28; 95% CI: 0.11, 0.71). CONCLUSIONS: BCCs on sun-protected sites arise as a result of excessive sun exposure, most likely combined with phenotypic susceptibility. The strong negative association with nevi also suggests that there are constitutional factors that underlie the propensity for BCCs to arise on these body sites.

Distinguishing intrinsic from extrinsic factors underlying firing rate saturation in human motor units.

During voluntary contraction, firing rates of individual motor units (MUs) increase modestly over a narrow force range beyond which little additional increase in firing rate is seen. Such saturation of MU discharge may be a consequence of extrinsic factors that limit net synaptic excitation acting on motor neurons (MNs) or may be due to intrinsic properties of the MNs. Two sets of experiments involving recording of human biceps brachii MUs were carried out to evaluate saturation. In the first set, the extent of saturation was quantified for 136 low-threshold MUs during isometric ramp contractions. Firing rate-force data were best fit by a saturating function for 90% of MUs recorded with a maximum rate of 14.8 ± 2.0 impulses/s. In the second set of experiments, to distinguish extrinsic from intrinsic factors underlying saturation, we artificially augmented descending excitatory drive to biceps MNs by activation of muscle spindle afferents through tendon vibration. We examined the change in firing rate caused by tendon vibration in 96 MUs that were voluntarily activated at rates below and at saturation. Vibration had little effect on the discharge of MUs that were firing at saturation frequencies but strongly increased firing rates of the same units when active at lower frequencies. These results indicate that saturation is likely caused by intrinsic mechanisms that prevent further increases in firing rate in the presence of increasing synaptic excitation. Possible intrinsic cellular mechanisms that limit firing rates of motor units during voluntary effort are discussed.

Number of motor units in human abductor hallucis.

Motor unit number was estimated for the human abductor hallucis (AH) muscle in 11 subjects by counting the number of increments in surface electromyographic responses to progressive increases in current-pulse amplitude applied to the muscle-nerve. The average motor unit count for AH (43) was substantially smaller than that estimated for other human muscles. Consequently, motor unit activity should be readily recordable up to high forces in AH, making it well suited for studies of recruitment and rate coding.

Abnormal PSA tests--delays in referral.

BACKGROUND: The main benefit of prostate specific antigen (PSA) testing is to help detect prostate cancer at an early, curable stage. Delays between the first abnormal PSA test and biopsy can undermine that benefit, but have not yet been studied. We investigated delays before biopsy together with associated PSA increases as an indicator of disease progression. METHODS: We identified 241 patients with a primary care referral because of an elevated PSA result (>4 ng/mL) and no previous prostate biopsy. Prostate specific antigen results and intervals between PSA testing, specialist clinic referral, appointment and biopsy were stratified by age. RESULTS: Median times between first abnormal PSA, referral, consultation and biopsy were modest but associated with increases in PSA. Extended delays (>20 months) between first abnormal PSA and referral occurred in 25% of younger men. A PSA result less than 10 ng/mL was the best predictor of a delay to refer. DISCUSSION: Rising PSA and possible cancer progression during investigation for prostate cancer suggest that prompt care is advisable.

Evaluation of plateau-potential-mediated 'warm up' in human motor units.

Spinal motor neurones can exhibit sustained depolarization in the absence of maintained synaptic or injected current. This phenomenon, referred to as a plateau potential, is due to the activation of monoamine-dependent persistent inward currents. Accordingly, activation of a plateau potential should result in a decrease in the excitatory synaptic drive required to activate a motor unit. This, in turn, has been suggested to cause a progressive decline in the muscle force at which motor units are recruited during repeated voluntary contractions. Such a progressive decrease in threshold force associated with preceding activation of a plateau potential is referred to as 'warm up'. Furthermore, activation of a plateau potential is thought to manifest itself as a decrease in the derecruitment force compared to recruitment force. Multiple muscles, however, can contribute to the detected force and their relative contributions may vary over time, which could confound measures of recruitment and derecruitment force. Therefore, the purpose of this study was to compare the recruitment and derecruitment forces of single motor units in the human extensor digitorum and tibialis anterior during repetitive triangular-force contractions in which the contributions of other muscles had been minimized. In both muscles, we found that the recruitment thresholds of single motor units were unchanged during repeated contractions, and that the derecruitment force was consistently greater than the recruitment force. These results suggest either that plateau potentials were not engaged (or were rapidly extinguished) under these experimental conditions or that changes in recruitment and derecruitment force are not suitable criteria for detecting them.

The positive effects of negative work: increased muscle strength and decreased fall risk in a frail elderly population.

BACKGROUND: The objective of this study was to determine if a chronic eccentric training intervention, i.e., negative work, could limit or even reverse sarcopenia and its related impairments and functional limitations. Is high-force eccentric training tolerable by elderly people and will it result in improved muscle size, strength, balance, and fall risk? METHODS: 21 frail elderly subjects (mean age, 80 years) experienced 11 weeks of lower extremity resistance training. The experimental eccentric (ECC) group (n=11) performed negative work while exercising on a high-force eccentric ergometer. The active "controls" performed traditional (TRAD) (n=10) lower extremity resistance exercises (weight training). Muscle fiber cross-sectional area and strength, balance, stair descending abilities, and fall risk were assessed prior to and following this intervention. RESULTS: All ECC subjects who started the negative work intervention completed the study and reported the training to be relatively effortless; they experienced minimal and transient muscle soreness. Both groups experienced a significant increase in muscle fiber cross-sectional area (ECC=60%, TRAD=41%). Only the ECC group experienced significant improvements in strength (60%), balance (7%), and stair descent (21%) abilities. The timed up and go task improved in both groups, but only the ECC group went from a high to a low fall risk. CONCLUSIONS: These data demonstrate that lower extremity resistance exercise can improve muscle structure and function in those with limited exercise tolerance. The greater strength increase following negative work training resulted in improved balance, stair descent, and fall risk only in the ECC group. Because low energy cost is coupled to high force production with eccentric exercise, this intervention may be useful for a number of patients that are otherwise unable to achieve high muscle forces with traditional resistance exercise.