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Aim: Obtain clinical consensus on factors impacting first-line prescribing for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). Materials & methods: A double-blinded, modified Delphi panel was employed. USA-based hematologists/oncologists who treat TIE patients with NDMM were selected as expert panelists. Results: Consensus was reached that patient frailty, performance status, comorbidities, treatment efficacy, and adverse event profile affect first-line prescribing. All panelists agreed it is important to use the most efficacious treatment first; 88% of panelists considered daratumumab-containing regimens the most efficacious. Panelists agreed treatment should be continued until progression while benefits outweigh risk. Conclusion: Findings reinforce the importance of using the most efficacious regimen upfront for TIE NDMM, and nearly all panelists considered daratumumab-containing regimens the most efficacious treatment.

Study Objective: The objective of this study was to define and characterize the unmet needs in the pharmacological management of insomnia., Methods: A systematic literature review was conducted to identify relevant literature reporting real-world evidence in insomnia, published from January 2009 to April 2020. Pharmacological treatments - both prescription (benzodiazepines, 'Z-drugs' and suvorexant) and off-label (antidepressants, antipsychotics, and antihistamines) - were considered., Results: Overall, 108 publications describing the humanistic ( n  = 59) and economic burden ( n  = 20) of insomnia, off-label treatment patterns ( n  = 28) and factors influencing treatment adherence or persistence ( n  = 8) were identified. A high prevalence of comorbid conditions was reported in patients with insomnia resulting in significantly lower health-related QoL compared to those with insomnia or a comorbidity alone. Current treatment options were associated with adverse events, including reduced sleep quality and next-day somnolence. An increased risk of accidents/injuries was also associated with insomnia and its treatment. Furthermore, safety concerns and perceived lack of efficacy for approved treatments have led to frequent off-label prescribing, despite a lack of clinical evidence of risk/benefit ratios. Safety concerns associated with benzodiazepines include risk of dependence, leading to prolonged treatment persistence and exacerbated adverse events, making them unsuitable for use in patients with chronic insomnia. Finally, the substantial economic burden of insomnia was evident, with reduced work productivity demonstrated in patients with insomnia compared to the general population., Conclusions: This review highlights a clear unmet need for insomnia therapies that improve sleep quality without resulting in next-day impairment and/or dependence.

To reduce morbidity and mortality associated with vaccine-preventable diseases (VPD), it is imperative that vaccination programs are implemented and prioritized throughout all stages of life across all populations. This study aimed to determine vaccine uptake and barriers to vaccination against VPDs among at-risk adult populations in the United States. We conducted a systematic literature review for articles published between January 2010 and June 2020 and identified 153 publications. The review identified 17 at-risk populations. Vaccine uptake was suboptimal among many populations, with factors including age, gender, and disease severity, associated with uptake. This review identified several barriers that impact vaccine uptake among at-risk populations, with concerns over safety, vaccine costs, lack of insurance, and lack of provider recommendation commonly reported across populations. Embracing a national life-course immunization framework that integrates developing policies, guidelines, and education would be a step to addressing these barriers.

Life-course immunization holds significant benefit for population health by reducing the burden of vaccine-preventable diseases (VPD) through vaccinating individuals at different stages and circumstances in life. The study aimed to determine the epidemiologic, clinical, economic, and societal burden of VPDs among at-risk adult subpopulations in the United States. A systematic literature review was conducted for articles published between January 2010 and June 2020, which identified 72 publications. There was heterogeneity in available epidemiology data, with the prevalence of VPDs ranging from 1.1% to 68.7%. Where the disease burden was described, outcomes were typically worse among high-risk subpopulations than in the general population. Several VPDs, including herpes zoster, meningococcal, and pneumococcal infections were associated with increased costs. This review suggests that subpopulations may not frequently interact with the healthcare system, or their risk factors may not be recognized by healthcare providers, and therefore individuals may not be appropriately targeted for vaccination.

Offline evaluation of recommender systems (RSs) mostly relies on historical data, which is often biased. The bias is a result of many confounders that affect the data collection process. In such biased data, user-item interactions are Missing Not At Random (MNAR). Measures of recommender system performance on MNAR test data are unlikely to be reliable indicators of real-world performance unless something is done to mitigate the bias. One widespread way that researchers try to obtain less biased offline evaluation is by designing new, supposedly unbiased performance metrics for use on MNAR test data. We investigate an alternative solution, a sampling approach . The general idea is to use a sampling strategy on MNAR data to generate an intervened test set with less bias - one in which interactions are Missing At Random (MAR) or, at least, one that is more MAR-like. An existing example of this approach is SKEW, a sampling strategy that aims to adjust for the confounding effect that an item's popularity has on its likelihood of being observed. In this paper, after extensively surveying the literature on the bias problem in the offline evaluation of RSs, we propose and formulate a novel sampling approach, which we call WTD; we also propose a more practical variant, which we call WTD_H. We compare our methods to SKEW and to two baselines which perform a random intervention on MNAR data. We empirically validate for the first time the effectiveness of SKEW and we show our approach to be a better estimator of the performance that one would obtain on (unbiased) MAR test data. Our strategy benefits from high generality (e.g. it can also be employed for training a recommender) and low overheads (e.g. it does not require any learning)., (© The Author(s) 2021.)

Introduction: Use of triptans for acute treatment of migraine is associated with insufficient efficacy and/or tolerability in approximately 30-40% of people. We conducted a systematic literature review (SLR) to synthesize definitions, terminology, subsequent treatment outcomes, and characteristics associated with this subpopulation., Methods: A comprehensive SLR was conducted to identify studies, published from Jan 1995 to May 2019, which focused on insufficient efficacy and/or tolerability to triptans., Results: Thirty-five publications were identified, of which 22 described randomized controlled trials and open-label studies, and 13 described observational studies. Across studies, multiple objectives and a high amount of variability in methodologies and outcomes were noted. The most commonly applied measures of efficacy were headache pain freedom and pain relief at 2 h. Ten studies assessed efficacy of switching or optimizing treatment in patients with historical insufficient efficacy or tolerability to previous triptan treatment and demonstrated varying levels of success. Factors associated with increased risk of triptan insufficient efficacy included severe baseline headache severity, photophobia, phonophobia, nausea, and depression., Conclusions: Irrespective of the methodology or definition used to identify people with insufficient efficacy and/or tolerability to triptans, study results support the assertion that a high unmet need remains for effective acute treatment of migraine.

This research investigated the spiritual care educational preparation that nursing students perceive they have received as they transition to practice. A survey using the Spirituality and Spiritual Care Rating Scale and interviews with senior BSN students at a Christian university demonstrated students' perceptions that their spiritual care education focused primarily on the practice of presence, emphasis on prayer, and the integration of faith in the curricula. Survey results showed a strong perception of readiness to provide spiritual care as graduate nurses.

Hydra represents a unique model system for the study of senescence, with the opportunity for the comparison of non-aging and induced senescence. Hydra maintains three stem cell lineages, used for continuous tissue morphogenesis and replacement. Recent work has elucidated the roles of the insulin/IGF-1 signaling target FoxO, of Myc proteins, and of PIWI proteins in Hydra stem cells. Under laboratory culture conditions, Hydra vulgaris show no signs of aging even under long-term study. In contrast, Hydra oligactis can be experimentally induced to undergo reproduction-associated senescence. This provides a powerful comparative system for future studies.

Existing data imply that the cnidarian Hydra vulgaris does not undergo senescence. In contrast, the related species Hydra oligactis shows increased mortality and physiological deterioration following sexual reproduction. Hydra thus offers the chance to study a striking difference in lifespan in members of the same genus. Adult Hydra possess three well-characterized stem cell populations, one of which gives rise to both somatic cells and gametes. The lack of senescence in Hydra vulgaris raises the question of how these stem cell populations are maintained over long periods of time. Investigation of the roles in Hydra of proteins involved in cellular stress responses in other organisms should provide insight into this issue. Proteins of particular interest include the Hsp70 family proteins and the transcription factor FoxO.

Background: In the face of changing environmental conditions, the mechanisms underlying stress responses in diverse organisms are of increasing interest. In vertebrates, Drosophila, and Caenorhabditis elegans, FoxO transcription factors mediate cellular responses to stress, including oxidative stress and dietary restriction. Although FoxO genes have been identified in early-arising animal lineages including sponges and cnidarians, little is known about their roles in these organisms., Methods/principal Findings: We have examined the regulation of FoxO activity in members of the well-studied cnidarian genus Hydra. We find that Hydra FoxO is expressed at high levels in cells of the interstitial lineage, a cell lineage that includes multipotent stem cells that give rise to neurons, stinging cells, secretory cells and gametes. Using transgenic Hydra that express a FoxO-GFP fusion protein in cells of the interstitial lineage, we have determined that heat shock causes localization of the fusion protein to the nucleus. Our results also provide evidence that, as in bilaterian animals, Hydra FoxO activity is regulated by both Akt and JNK kinases., Conclusions: These findings imply that basic mechanisms of FoxO regulation arose before the evolution of bilaterians and raise the possibility that FoxO is involved in stress responses of other cnidarian species, including corals.

Purpose: To assess, among children with low literacy and poor stereoacuity, the efficacy of two intervention programs on child vision and education compared to a control program., Methods: Eighty-eight children aged 8 to 13 years who had reading problems, and demonstrated poor stereoacuity as measured by the Titmus stereocircle test (> 100 seconds arc) or computerized assessment were randomized to one of two intervention programs: Lawson vision or Phono-Graphix, or a control group: Parental Literacy Support. Vision (Lang test, visual acuity, convergence insufficiency symptom survey) and education assessments (Woodcock Reading Mastery Tests-Revised) were conducted at baseline, intervention end (10 weeks), and 36 weeks. Analysis used intention to treat multi-level models., Results: Compared to the parental literacy support group, convergence insufficiency symptoms were reduced 36 weeks post-randomization amongst those receiving the Lawson orthoptic intervention (mean difference -5.55; 95% confidence interval (CI): -11.1 to -0.05, P < 0.05). Stereoacuity, measured by the Lang test, improved for both the Lawson and Phono-Graphix interventions compared to the parental literacy support group (-1.01; 95% CI: -1.6 to -0.4, P = 0.001, and -0.77; 95% CI: -1.4 to -0.2, P = 0.01). At the 36 week follow-up assessment, word identification had also improved for the Lawson and Phono-Graphix groups but other educational outcomes did not improve., Conclusion: A formal randomized control trial was feasible in this setting. Intervention among children with poor stereoacuity and low literacy produced small improvements in stereopsis and convergence insufficiency symptom scores. Further randomized control trials should be conducted to clarify the role of orthoptic intervention on literacy in selected child populations.

Objectives: To document the use of sedation for refractory symptoms in patients admitted to an independent palliative care unit., Method: A prospective descriptive study., Setting: The 7-bed inpatient unit at Sungardens Hospice, Pretoria., Subjects: Patients who required sedation for refractory symptoms in addition to normal palliative care treatment between January and June 2002., Findings: Twenty of 100 consecutive patients admitted required sedation. All had advanced cancer. Their mean age was 68 years. Thirty-six per cent were men and 64% women., Indications: Agitated delirium was the most common reason (45%) for using sedation, followed by intractable vomiting due to inoperable malignant intestinal obstruction in 25% of patients. Three patients with persistent convulsions or myoclonic jerking and 2 patients with severe refractory dyspnoea required some sedation. Intractable pain was the main reason for sedation in only 1 patient., Survival: Mean survival following the start of sedation was 92 hours/3.8 days (range 6 - 369 hours/0.25 - 19.4 days). The combined mean survival recorded in 9 other studies was 57 hours/2.4 days (range 36 - 93.6 hours/1.5 - 3.9 days)., Medication: The main drugs used for sedation were midazolam and haloperidol. The mean dosage for midazolam was 18.5 mg/24 hours (range 7.5 - 40 mg) and for haloperidol 8 mg/24 hours (range 5 - 10 mg). For pain relief the mean daily dose of parenteral morphine was 76 mg (range 15 - 260 mg)., Conclusion: Use of sedation for the relief of refractory symptoms at Sungardens Hospice is in line with several studies reported in the international literature.

Identification of chromosomal markers for rapid detection of Bacillus anthracis is difficult because significant chromosomal homology exists among B. anthracis, Bacillus cereus, and Bacillus thuringiensis. We evaluated the bacterial gyrA gene as a potential chromosomal marker for B. anthracis. A real-time PCR assay was developed for the detection of B. anthracis. After analysis of the unique nucleotide sequence of the B. anthracis gyrA gene, a fluorescent 3' minor groove binding probe was tested with 171 organisms from 29 genera of bacteria, including 102 Bacillus strains. The assay was found to be specific for all 43 strains of B. anthracis tested. In addition, a test panel of 105 samples was analyzed to evaluate the potential diagnostic capability of the assay. The assay showed 100% specificity, demonstrating the usefulness of the gyrA gene as a specific chromosomal marker for B. anthracis.

During Hydra oogenesis, an aggregate of germ cells differentiates into one oocyte and thousands of nurse cells. Nurse cells display a number of features typical of apoptotic cells and are phagocytosed by the growing oocyte. Yet, these cells remain unchanged in morphology and number until hatching of the polyp, which can occur up to 12 months later. Treatments with caspase inhibitors can block oocyte development during an early phase of oogenesis, but not after nurse cell phagocytosis has taken place, indicating that initiation of nurse cell apoptosis is essential for oocyte development. The genomic DNA of the phagocytosed nurse cells in the oocyte and embryo shows large-scale fragmentation into 8- to 15-kb pieces, but there is virtually none of the internucleosomal degradation typically seen in apoptotic cells. The arrested nurse cells exhibit high levels of peroxidase activity and are prevented from entering the lysosomal pathway. After hatching of the polyp, apoptosis is resumed and the nurse cells are degraded within 3 days. During this final stage, nurse cells become TUNEL-positive and enter secondary lysosomes in a strongly degraded state. Our results suggest that nurse cell apoptosis consists of caspase-dependent and caspase-independent phases. The independent phase can be arrested at an advanced stage for several months, only to resume after the primary polyp hatches.

Methadone is a potent synthetic opioid analgesic best known in Australia as maintenance therapy for narcotic addicts. Acceptance of methadone in cancer pain management is limited by a poor understanding of its pharmacokinetics and confusion about dosage. Many opioid conversion charts underestimate the potency of methadone, resulting in the risk of toxicity. Methadone is a valuable addition to the armamentarium of clinicians treating severe cancer pain, particularly neuropathic pain, that is poorly responsive to opioids or where opioid side effects are unacceptable.

Axial patterning of the aboral end of the hydra body column was examined using expression data from two genes. One, shin guard, is a novel receptor protein-tyrosine kinase gene expressed in the ectoderm of the peduncle, the end of the body column adjacent to the basal disk. The other gene, manacle, is a paired-like homeobox gene expressed in differentiating basal disk ectoderm. During regeneration of the aboral end, expression of manacle precedes that of shin guard. This result is consistent with a requirement for induction of peduncle tissue by basal disk tissue. Our data contrast with data on regeneration of the oral end. During oral end regeneration, markers for tissue of the tentacles, which lie below the extreme oral end (the hypostome), are detected first. Later, markers for the hypostome itself appear at the regenerating tip, with tentacle markers displaced to the region below. Additional evidence that tissue can form basal disk without passing through a stage as peduncle tissue comes from LiCl-induced formation of patches of ectopic basal disk tissue. While manacle is ectopically expressed during formation of basal disk patches, shin guard is not. The genes examined also provide new information on development of the aboral end in buds. Although adult hydra are radially symmetrical, expression of both genes in the bud's aboral end is initially asymmetrical, appearing first on the side of the bud closest to the parent's basal disk. The asymmetry can be explained by differences in positional information in the body column tissue that evaginates to form a bud. As predicted by this hypothesis, grafts reversing the orientation of evaginating body column tissue also reverse the orientation of asymmetrical gene expression., (Copyright 2000 Academic Press.)

Several studies have provided strong, but indirect evidence that signalling through pathways involving protein kinase C (PKC) plays an important role in morphogenesis and patterning in Hydra. We have cloned a gene (HvPKC2) from Hydra vulgaris which encodes a member of the nPKC subfamily. In adult polyps, HvPKC2 is expressed at high levels in two locations, the endoderm of the foot and the endoderm of the hypostomal tip. Increased expression of HvPKC2 is an early event during head and foot regeneration, with the rise in expression being restricted to the endodermal cells underlying the regenerating ends. No upregulation is observed if regenerates are cut too close to the head to form a foot. Elevated expression of HvPKC2 is also observed in the endoderm underlying lithium-induced ectopic feet. A dynamic and complex pattern of expression is seen in developing buds. Regeneration of either head or foot is accompanied by an increase in the amount of PKC in both soluble and particulate fractions. An increase in the fraction of PKC activity which is membrane-bound is specifically associated with head regeneration. Taken together these data suggest that patterning of the head and foot in Hydra is controlled in part by the level of HvPKC2 expression, whilst head formation is accompanied by an in vivo activation of both calcium-dependent and independent PKC isoforms.

The notion that members of the phylum Myxozoa Grassé, 1970 do not properly belong in classifications of protists has frequently been suggested because the infective spores of these parasites are not unicellular. Systematists have failed to be decisive about myxozoan phylogenetic affinities, either finding the suggestion of a cnidarian connection to be preposterous or considering the recent suggestion of a relationship with nematodes to be an obvious failure of molecular phylogenetics. Thus, the group has remained in classifications as a protistan phylum in its own right. The ultrastructure of the development of myxozoans was critically re-examined in order to more fully explore the possibility of morphological synapomorphies with metazoan taxa. These morphological characters, in combination with small ribosomal subunit gene sequences, were used in a phylogenetic analysis in order to assess myxozoan origins. The results unequivocally support the inclusion of myxozoans as a clade of highly derived parasitic cnidarians, and as sister taxon to the narcomedusan Polypodium hydriforme. Reassessment of myxozoans as metazoans reveals terminal differentiation, typical metazoan cellular junctions, and collagen production. Their "polar capsules" are redescribed as typical nematocysts bearing atrichous isorhiza. Insofar as taxa cannot be contained within other taxa of equal rank, the phylum Myxozoa is abandoned and it is recommended that the group as a whole be removed from all protistan classifications and placed in a more comprehensive cnidarian system.

Octreotide is a synthetic analogue of somatostatin with a longer half-life than the native peptide. It has been used extensively in a variety of clinical settings for some years. More recently, its uses in malignant disease processes have been studied and it is proving to be an excellent addition to the palliative care pharmacy. We look at the current uses of octreotide for the palliation of malignant disease with particular emphasis on inoperable malignant bowel obstruction. Octreotide may palliate nausea and vomiting in this distressing condition when other therapies fail. Octreotide may also control severe diarrhoea and help in the closure of fistulae from benign and malignant conditions. It has unique analgesic properties. Radio-labelled isotopes of octreotide may be used to image some tumours. Recently, it has also shown potential in anti-cancer treatment.

The validity of any comparative study is dependent on the reliability of the identification of the samples in the study. Not all researchers are experts in the field of identification of samples, nor do all researchers have quick and ready access to expert systematists who can accomplish the task of identification. The importance of verification of sample identity for comparative studies is vital. We describe several methods by which researchers can obtain and identify samples from the wild, and we suggest methods by which voucher samples can be obtained for future reference to these collected samples. We outline alternatives to collection of samples from the wild, such as purchase from stock centers and biological supply companies. Museum collections can also be extremely helpful in obtaining complete organismal samples for comparative studies.

When measuring human leukocyte HMG-CoA reductase activity, special care must be taken to prevent erythrocyte contamination of the leukocyte layer during isopycnic centrifugation. Contamination during leukocyte isolation and subsequent erythrocyte lysis during NH4Cl treatment results in increased leukocyte microsomal HMG-CoA reductase activity. Increased enzyme activity is not due to enzyme dephosphorylation, thiol-disulfide reduction or increased enzyme protein concentration. Leukocyte populations containing granulocytes appear to be most sensitive. Prevention of erythrocyte contamination during isopycnic centrifugation should aid in accurate measurement of human leukocyte HMG-CoA reductase activity.

The development and implementation of a comprehensive industrial hygiene and safety program is a complex activity for which there does not exist a uniform code or set of guidelines. Although the ultimate goal of such a program is to provide for the welfare of the employee through the use of engineering control and other preventive measures, there is great variation among business establishments on methods necessary to attain this result. Factors which contribute to this variation usually are: type of industry, management philosophy and size of the business establishment. This paper addresses many key elements integral to this activity such as justification and philosophy, organizational reporting relationships, interfunctional communication, technical and personnel requirements and program performance indicators.