Sleep disturbance in patients with advanced cancer

Sleep is a complex process, acknowledged to be essential for health and wellbeing. Sleep disturbance is reported to be a significant problem for patients across the cancer care trajectory, including those in the palliative phase of illness. This paper reviews the literature specific to sleep disturbance in patients with advanced cancer. The Human Response to Illness model, which is consistent with the central tenets of palliative care philosophy, provides a valuable framework to examine and organize the current knowledge related to sleep disturbance. The four perspectives of this biopsychosocial nursing model--physiology, pathophysiology, behavioural and experiential, as well as the personal and environmental factors--offer a broad perspective to better understand this multidimensional symptom and create a strong foundation for nursing care and future research directions.     

Epidemiology of spinal muscular atrophy caused by SMN1 deletions in Maritime Canada

Spinal muscular atrophy (SMA), caused primarily by deletions in SMN1, leads to progressive loss of lower motor neurons. Newborn screening for SMA is under consideration for the Maritime Newborn Screening Program. The incidence of this disease has not been explored in Maritime Canada which includes the provinces of Nova Scotia (NS), New Brunswick (NB), and Prince Edward Island (PEI). In this retrospective chart review, patients were identified from the IWK Clinical Genomics Lab and Maritime Medical Genetics Service databases for SMN1 genetic testing between 2000 and 2020. The incidence of SMA in Maritime Canada was 1:11,900. Among patients born between 2000 and 2020, NB and PEI had lower proportions of type 1 SMA (12% and 0%, respectively) when compared to NS (50%). The majority of type 1 patients had 2 copies of SMN2, the majority of type 2 patients had 3 copies, and the majority of type 3 patients had 4 copies. There was a delay to molecular diagnosis for all subtypes, longest in type 3. This study provides the best available SMA epidemiology in Maritime Canada and expands our understanding of the pattern of disease severity relative to SMN2 copy number in this region.     

Papanicolaou smears induce partial immunity against sexually transmitted viral infections

BACKGROUND: In a case-control study of hormonal contraceptives and invasive cervical cancer, an unexpected finding was a substantial decline in the prevalence of high-risk human papillomavirus (HPV) infection according to the lifetime number of Pap smears received. Here we assess the risk of 3 sexually transmitted viral infections -- herpes simplex virus 2 (HSV2), HPV, and human immunodeficiency virus (HIV) 1 and 2 -- in relation to the lifetime receipt of Pap smears. METHODS: Stored sera taken from 1540 controls were tested for HSV2 and HIV; cervical scrapings were tested for HPV. Confounder-adjusted odds ratios for the lifetime receipt of Pap smears were estimated, relative to never having had a Papanicolau test. RESULTS: For ever-receipt of a Papanicolau test, the odds ratios for HSV2 and HPV were 0.7 (95% confidence interval = 0.5-0.9) and 0.5 (0.3-0.7), respectively, and there were dose-response trends according to the lifetime number of Pap smears received (test for trend P = 0.02 and 0.04, respectively). For HSV2 the odds ratios according to last receipt declined from 0.8 for 10 or more years previously to 0.4 for <1 year previously (trend P = 0.002). For HPV the ORs were 0.4 (0.3-0.7) for last receipt 5-9 years previously and 0.5 (0.4-0.8) for less than 5 years previously; for HIV the odds ratio for last receipt less than 5 years previously was 0.4 (0.3-0.9).For HSV2 and HIV the crude odds ratio estimates were systematically lower than the adjusted estimates, and residual confounding cannot be ruled out. In particular, the true number of sexual partners may have been under-reported, and there was no information on the sexual activity of the male partners, or on other health behaviors of the women or their partners. CONCLUSION: We hypothesize that Pap smears may provoke a short-term immune response against sexually transmitted viral infections.     

Tissue Distribution of Polychlorinated Biphenyls and Organochlorine Pesticides and Potential Toxicity to Alaskan Northern Fur Seals Assessed Using PCBs Congener Specific Mode of Action Schemes

The fur seal (Callorhinus ursinus) population has decreased in their primary breeding grounds in the Bering Sea; contamination is among suspected causes. Our goal was to better understand the extent of contamination of seal tissues with certain organochlorine compounds by measuring the concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in fur seal tissues from St. Paul Island, to gain a better perspective of tissue congener distribution and to evaluate the observed PCB levels against toxicologically significant levels for modes of action. Concentrations of 145 PCB congeners (∑₁₄₅PCBs) and 12 OCPs were measured with gas chromatography–ion trap mass spectrometry in 8 different tissues of 10 male northern fur seals. The mean concentrations of ∑OCPs [in ng/g lipid weight (lw)] were 1180 in blubber, 985 in the heart, 1007 in the liver, 817 in the kidney, 941 in muscle, 660 in reproductive tissues, 204 in the brain, and 322 in the lung. The mean concentrations of ∑₁₄₅PCBs (in ng/g lw) were 823 in blubber, 777 in the liver, 732 in the heart, 646 in reproductive tissues, 638 in muscle, 587 in the kidney, 128 in the lung, and 74.3 in brain tissues. Concentrations of PCBs affecting the aryl hydrocarbon receptor expressed as total PCB toxic equivalents (∑PCB-TEQs) ranged from 0.3 to 545 pg/g lw for the various tissues. The major contributors to ∑PCB-TEQs are CB-118 in muscle, brain, lung, kidney, and liver, CB-126 in blubber, and CB-118 and CB-126 equally in the heart and reproductive tissues. Concentrations of PCBs affecting Ca²⁺ homeostatsis expressed as the neurotoxic equivalent (NEQ) showed ∑PCB-NEQs ranged from 17.7 to 215 ng/g lw in all tissues. Although no composite measure of perturbation of thyroid function is available, sufficient amounts of congeners with high binding to the thyroxine transport system were present to warrant consideration of this mode of action in future studies. Analyses of 145 PCBs and mode of action evaluation suggest that PCB contamination could potentially exert an effect on the Alaskan northern fur seal population although the PCB concentrations have been decreasing in the fur seals over the last decade.     

Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation

Four direct thrombin inhibitors (DTIs), lepirudin, bivalirudin, argatroban, and melagatran, differ in their ability to prolong the prothrombin time (PT). Paradoxically, the DTI in clinical use with the lowest affinity for thrombin (argatroban) causes the greatest PT prolongation. We compared the effects of these DTIs on various clotting assays and on inhibition of human and bovine factor Xa (FXa). On a mole-for-mole basis, lepirudin was most able to prolong the PT, activated partial thromboplastin time (APTT), and thrombin clotting time (TCT), whereas argatroban had the least effect. At concentrations that doubled the APTT (argatroban, 1 micromol/l; melagatran, 0.5 micromol/l; bivalirudin, 0.25 micromol/l; lepirudin, 0.06 micromol/l), the rank order for PT prolongation was: argatroban > melagatran > bivalirudin > lepirudin. Although the Ki's associated with inhibition of human FXa by melagatran (1.4 micromol/l) and argatroban (3.2 micromol/l) approach their therapeutic concentrations, inhibition of FXa did not appear to be a major contributor to PT prolongation, since argatroban also prolonged the PT of bovine plasma (despite a Ki for bovine FXa of 2,600 micromol/l). Only melagatran inhibited prothrombinase-bound FXa. We conclude that the differing effects of the DTIs on PT prolongation are primarily driven by their respective molar plasma concentrations required for clinical effect. DTIs with a relatively low affinity for thrombin require high plasma concentrations to double the APTT; these higher plasma concentrations, in turn, quench more of the thrombin generated in the PT, thereby more greatly prolonging the PT.     

Quantitative assessment of colorectal cancer perfusion using MDCT: inter- and intraobserver agreement

OBJECTIVE: The objective of our study was to determine inter- and intraobserver agreement of MDCT colorectal cancer perfusion measurements. SUBJECTS AND METHODS: Thirty-one patients (17 men, 14 women; median age, 69 years) with proven colorectal cancer were examined prospectively using MDCT. A 65-sec dynamic study (cine mode, 4 x 5 mm collimation) was acquired through the tumor after i.v. contrast administration (100 mL of iopamidol 350, 5 mL/sec). Tumor blood volume, blood flow, mean transit time, and permeability measurements were determined by two independent observers using commercial software. Inter- and intraobserver agreement was assessed using the Bland-Altman test. RESULTS: The mean difference for interobserver agreement (95% limits of agreement) was -0.81 mL/100 g tissue (-3.14 to 1.52); -9.94 mL/100 g tissue/min (-51.43 to 32.65); -1.09 sec (-7.05 to 4.86); and -2.90 mL/100 g tissue/min (-11.48 to 5.68) for blood volume, blood flow, mean transit time, and permeability, respectively. The intraclass correlation coefficient was 0.83, 0.89, 0.89, and 0.80, respectively. The mean difference for intraobserver agreement (95% limits of agreement) was 0.12 mL/100 g tissue (-1.90 to 2.14); 0.02 mL/100 g tissue/min (-13.13 to 13.17); -0.19 sec (-3.19 to 2.81); and 0.00 mL/100 g tissue/min (-2.45 to 2.45) for observer 1 and 0.26 mL/100 g tissue (-1.46 to 1.98); 4.47 mL/100 g tissue/min (-26.65 to 35.59); -0.21 sec (-2.48 to 2.06); 1.08 mL/100 g tissue/min (-4.92 to 7.08) for observer 2. The intraclass correlation coefficient was 0.86, 0.98, 0.97, 0.98 for observer 1 and 0.93, 0.96, 0.99, and 0.94, respectively, for observer 2. CONCLUSION: There is greater inter- than intraobserver agreement for CT vascular perfusion measurements of primary colorectal cancer, which must be addressed for reliable clinical application in therapeutic monitoring.     

Interferon-inducible Mx proteins in fish

Summary: Mx proteins are members of a family of hiterferon-inducible genes expressed when cells are treated with double-stranded RNA or virus infection. These proteins are important components of the antiviral response and form the first line of the body's defense against virus infections. The exact mechanism of action for these proteins has not been discovered, but mice missing the Mx genes are extremely sensitive to influenza virus infection. Mammals have between two and three Mx genes whose functions may vary with regard to the inhibition of a specific virus, cellular localization, and activity. The cDNA of three rainbow trout Mx proteins has been cloned and a comparison of their sequences with that of avian and mammalian species reveals striking conservation of domains. They all maintain the tripartite ATP/GTP binditig domain and the dynamin family signature in the amino terminal half of the protein. In the carboxyl terminal half of the Mx proteins are che Iocalization signals and the leucine zipper motifs which account for the trimerization of Mx in the cell. Like the rat and human Mx proteins, the different trout Mx proteins exhibit distinctly different immunohistochemical staining patterns in cells transfected with plasmids expressing RBTMx1, RBTMx2, or RBTMx3, To date, the antiviral function of the trout Mx proteins has not been satisfactorily established.     

On-site training in applied muscle tension to reduce vasovagal reactions to blood donation

Vasovagal reactions significantly complicate the blood collection process and, more importantly, discourage people who might otherwise donate blood many times from returning. Applied muscle tension is a simple behavioral technique that may reduce vasovagal reactions by maintaining blood pressure. It has been successfully used to treat patients with blood and injury phobias, but has not been applied in the more general, time-limited context of blood collection clinics. Thirty-seven inexperienced blood donors (maximum number of prior donations = 2) attending mobile blood collection clinics were asked to practice applied tension after watching a 2-min instructional video presented on a notebook computer. They were compared with 94 untreated donors with similar donation experience and 47 more experienced blood donors. Treatment reduced the number of symptoms reported on a postdonation questionnaire. It also significantly reduced the amount of medical treatment required (chair reclining) among those who practiced applied tension for the entire period they were in the donation chair.     

Characterization of the First SARS-CoV-2 Isolates from Aotearoa New Zealand as Part of a Rapid Response to the COVID-19 Pandemic

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has wreaked havoc across the globe for the last two years. More than 300 million cases and over 5 million deaths later, we continue battling the first real pandemic of the 21st century. SARS-CoV-2 spread quickly, reaching most countries within the first half of 2020, and New Zealand was not an exception. Here, we describe the first isolation and characterization of SARS-CoV-2 variants during the initial virus outbreak in New Zealand. Patient-derived nasopharyngeal samples were used to inoculate Vero cells and, three to four days later, a cytopathic effect was observed in seven viral cultures. Viral growth kinetics was characterized using Vero and VeroE6/TMPRSS2 cells. The identity of the viruses was verified by RT-qPCR, Western blot, indirect immunofluorescence assays, and electron microscopy. Whole-genome sequences were analyzed using two different yet complementary deep sequencing platforms (MiSeq/Illumina and Ion PGM™/Ion Torrent™), classifying the viruses as SARS-CoV-2 B.55, B.31, B.1, or B.1.369 based on the Pango Lineage nomenclature. All seven SARS-CoV-2 isolates were susceptible to remdesivir (EC₅₀ values from 0.83 to 2.42 µM) and β-D-N⁴-hydroxycytidine (molnupiravir, EC₅₀ values from 0.96 to 1.15 µM) but not to favipiravir (>10 µM). Interestingly, four SARS-CoV-2 isolates, carrying the D614G substitution originally associated with increased transmissibility, were more susceptible (2.4-fold) to a commercial monoclonal antibody targeting the spike glycoprotein than the wild-type viruses. Altogether, this seminal work allowed for early access to SARS-CoV-2 isolates in New Zealand, paving the way for numerous clinical and scientific research projects in the country, including the development and validation of diagnostic assays, antiviral strategies, and a national COVID-19 vaccine development program.     

Psychosocial outcomes 1-7 years after comprehensive milieu-oriented neurorehabilitation: the role of pre-injury status

Primary objective: To explore pre-injury variables related to post-discharge psychosocial status and identify factors related to work and driving outcomes.

Methods and procedures: Ninety-three brain-injured patients attended a holistic milieu-oriented neurorehabilitation program and were contacted 1-7 years post-discharge.

Experimental interventions: Questionnaire data addressing pre-injury and post-injury work, driving, income, marital status and living situation.

Main outcomes and results: 74.3% were involved in competitive work and/or school with 86.0% productive at follow-up. Post-injury income decreased significantly compared with pre-injury levels. Pre-injury relationship status did not differ significantly from post-injury; 81.1% remaining in a stable relationship or married at follow-up. Pre-injury and post-injury accident rates were related; 73.1% drove at follow-up. Higher education, non-right hemispheric injury, shorter treatment length and return to work related to driving. Younger age, higher education, non-right hemispheric injury and driving post-injury related to positive work status.

Conclusions: Pre-injury psychosocial data provide an important context for understanding post-discharge outcome after brain injury. Holistic milieu-oriented rehabilitation facilitates long-term successful work, driving and relationship stability.