A Meta-Ethnographic Review of Paid Staff and Volunteers Working together in Palliative Care.

CONTEXT: Volunteers in palliative care settings are an essential part of care provision for patients and those important to them. Effective collaboration between volunteers and paid staff has been regarded as an important element of successful working, however, at times failures in coordination, information sharing and tensions within teams have been highlighted. OBJECTIVES: To explore the views expressed by volunteers and paid staff about their experiences of working together in palliative care settings. METHODS: A systematic exploration of qualitative research using a meta-ethnographic approach. PsycINFO, CINAHL, Medline Complete, and AMED databases were searched from inception to December 2021 for the concepts "volunteers" and "palliative care." Repeated in-depth reading and appraisal of papers identified metaphors and concepts, providing new interpretations. RESULTS: Included papers (n = 14) enabled the construction of five storylines: 1) "we are the cake, and they are the cream": understanding the volunteer role-separate, but part of a whole. 2) "…we don't know what's wrong with people but sometimes we need to know": access to information and importance of trust. 3) "everybody looks out for each other": access to paid staff and their support. 4) "...we don't meddle in the medical": boundaries. 5) "it's the small things that the staff does for me that makes me feel good about my work": sense of value and significance. CONCLUSIONS: For effective working relationships between paid staff and volunteers, proactive engagement, recognition of each other's role and contribution, mutual sharing of information, and intentional interaction between both groups is needed.

Molecular correlates of muscle spindle and Golgi tendon organ afferents.

Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output.

Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders.

Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells. Interaction of NSKI TOP1362 with the kinases was evaluated in ATP-dependent Z-LYTE and competition binding assays. Anti-inflammatory activity was assessed in human peripheral blood mononuclear cells and primary macrophages. In an endotoxin-induced uveitis (EIU) study, lipopolysaccharide (LPS) was administered intravitreally to Lewis rats. TOP1362, dexamethasone, or vehicle was administered topically, and inflammatory cytokine levels were measured 6 hours after LPS injection. Results: HCE cells from DED patients showed significantly increased expression of p38α, spleen tyrosine kinase (Syk), Src, lymphocyte-specific protein tyrosine kinase (Lck), interleukin one beta (IL-1ß), interleukin eight (IL-8), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9). TOP1362 strongly inhibited the kinase targets p38α, Syk, Src, and Lck, blocked the rise in p38α expression in hyperosmolar Chang cells, and potently reduced inflammatory cytokine release in cellular models of innate and adaptive immunities. In the EIU model, TOP1362 dose-dependently attenuated the LPS-induced rise in inflammatory cell infiltration and ocular cytokine levels with efficacy comparable to that of dexamethasone. Conclusions: TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.

Effect of tear supplements on signs, symptoms and inflammatory markers in dry eye.

PURPOSE: Three tear supplements were compared for their effects on the signs, symptoms and inflammatory status of subjects with dry eye disease. Assessments were made before and after both 2 and 4 weeks of treatment. METHODS: In this masked, randomized, 3-way crossover trial, eighteen dry eye subjects were recruited. At each visit, symptoms, tear evaporation rate, stability and osmolarity were measured and tear samples were analyzed for 7 inflammatory markers, using multiplex immunoassays. The 3 treatments included carboxymethylcellulose-glycerine-castor oil (CGC), carboxymethylcellulose (CMC) and hydroxypropyl guar (HPG). The CGC and HPG drops are emulsified lipids; CGC also contains osmoprotectants. The CMC drop is a standard aqueous polymeric supplement. RESULTS: Significant improvements were seen in symptoms (OSDI) and tear stability (NITBUT) with all 3 treatments at 4 weeks. At 4 weeks post-CGC, 6 out of 7 biomarkers demonstrated a >25% reduction (in 40% of subjects). The same reduction (>25%) was seen in 10% of the subjects for CMC and in none of the subjects for HPG. No significantly different change to either evaporation rate or tear osmolarity was found following any of the three treatments. CONCLUSIONS: In this study, the CGC treatment resulted in the greatest reduction in ocular biomarkers of inflammation, while all 3 treatments reduced symptoms and improved tear stability. These results indicate that subject-perceived symptomatic improvements are not necessarily associated with a reduction in objective measures of inflammation.

Care solution effects on contact lens in vivo wettability.

BACKGROUND: The aim of the study was to evaluate the effect of care solutions on contact lens in vivo wettability using Doane's interferometric technique. METHODS: Thirteen subjects (aged 26.6 ± 6.3 years) participated for contact lens wettability evaluation after soaking in five care solutions namely Opti-Free EverMoist (now called puremoist), Opti-Free Express (Alcon), COMPLETE (AMO), ReNu and Biotrue (Bausch & Lomb). A new pair of lenses was soaked in the solutions for eight hours (prior to wear) or taken directly from pack solutions (as control) and worn by the subjects. The total number of pairs of lenses tested was 13 by six (78 lenses; 13 pairs of lenses wetted in five care solutions plus the pack solution). Doane's interferometer was used to capture images of the pre-lens film on a single type of contact lens, Acuvue Oasys (Johnson & Johnson). The lens in vivo wettability was evaluated after 15 minutes and eight hours of wear by each subject. Four parameters: onset latency, drying duration, maximum speed and peak latency were used to assess the lens wettability. RESULTS: After eight hours, the solutions showing significant reduction in contact lens wettability were the following. For onset latency: Pack solution, Biotrue Opti-Free EverMoist and Express; for drying duration: pack solution, ReNu and Opti-Free EverMoist; for peak latency; pack solution, Biotrue and Opti-Free EverMoist. Regarding the maximum speed, lenses soaked in Pack solution, ReNu and Opti-Free EverMoist showed a significant increase (worsening). The comparative study showed that there were significant differences among the performance of the care solutions. CONCLUSION: This novel thin film interferometric technique was able to measure, objectively, contact lens in vivo wettability, following the use of care solutions. COMPLETE was the only solution that showed no significant change in the lens wettability (with the all parameters) between the initial and the end of day.

Infrared vibrational spectroscopy: a rapid and novel diagnostic and monitoring tool for cystinuria.

Cystinuria is the commonest inherited cause of nephrolithiasis (~1% in adults; ~6% in children) and is the result of impaired cystine reabsorption in the renal proximal tubule. Cystine is poorly soluble in urine with a solubility of ~1 mM and can readily form microcrystals that lead to cystine stone formation, especially at low urine pH. Diagnosis of cystinuria is made typically by ion-exchange chromatography (IEC) detection and quantitation, which is slow, laboursome and costly. More rapid and frequent monitoring of urinary cystine concentration would significantly improve the diagnosis and clinical management of cystinuria. We used attenuated total reflection - Fourier transform infrared spectroscopy (ATR-FTIR) to detect and quantitate insoluble cystine in 22 cystinuric and 5 healthy control urine samples. Creatinine concentration was also determined by ATR-FTIR to adjust for urinary concentration/dilution. Urine was centrifuged, the insoluble fraction re-suspended in 5 µL water and dried on the ATR prism. Cystine was quantitated using its 1296 cm-1 absorption band and levels matched with parallel measurements made using IEC. ATR-FTIR afforded a rapid and inexpensive method of detecting and quantitating insoluble urinary cystine. This proof-of-concept study provides a basis for developing a high-throughput, cost-effective diagnostic method for cystinuria, and for point-of-care clinical monitoring.

Effects of the Hydration State on the Mid-Infrared Spectra of Urea and Creatinine in Relation to Urine Analyses.

When analyzing solutes by Fourier transform infrared (FT-IR) spectroscopy in attenuated total reflection (ATR) mode, drying of samples onto the ATR crystal surface can greatly increase solute band intensities and, therefore, aid detection of minor components. However, analysis of such spectra is complicated by the existence of alternative partial hydration states of some substances that can significantly alter their infrared signatures. This is illustrated here with urea, which is a dominant component of urine. The effects of hydration state on its infrared spectrum were investigated both by incubation in atmospheres of fixed relative humidities and by recording serial spectra during the drying process. Significant changes of absorption band positions and shapes were observed. Decomposition of the CN antisymmetric stretching (νas) band in all states was possible with four components whose relative intensities varied with hydration state. These correspond to the solution (1468 cm(-1)) and dry (1464 cm(-1)) states and two intermediate (1454 cm(-1) and 1443 cm(-1)) forms that arise from specific urea-water and/or urea-urea interactions. Such intermediate forms of other compounds can also be formed, as demonstrated here with creatinine. Recognition of these states and their accommodation in analyses of materials such as dried urine allows more precise decomposition of spectra so that weaker bands of diagnostic interest can be more accurately defined.

A Phase 1, Multi-Center, Open-Label, Dose-Escalation Study of 131I-CLR1404 in Subjects with Relapsed or Refractory Advanced Solid Malignancies.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues' retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.

Conformational changes during pore formation by the perforin-related protein pleurotolysin.

Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly. The major conformational changes in PlyB are a ∼70° opening of the bent and distorted central ß-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane ß-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trapped prepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of ß-sheet unbending. The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2. Following their release we propose that the transmembrane regions assemble into ß-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted ß-barrel. The intermediate structures of the MACPF domain during refolding into the ß-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function.

Lynx1 supports neuronal health in the mouse dorsal striatum during aging: an ultrastructural investigation.

Nicotinic acetylcholine receptors have been shown to participate in neuroprotection in the aging brain. Lynx protein modulators dampen the activity of the cholinergic system through direct interaction with nicotinic receptors. Although lynx1 null mutant mice exhibit augmented learning and plasticity, they also exhibit macroscopic vacuolation in the dorsal striatum as they age, detectable at the optical microscope level. Despite the relevance of the lynx1 gene to brain function, little is known about the cellular ultrastructure of these age-related changes. In this study, we assessed degeneration in the dorsal striatum in 1-, 3-, 7-, and 13-month-old mice, using optical and transmission electron microscopy. We observed a loss of nerve fibers, a breakdown in nerve fiber bundles, and a loss of neuronal nuclei in the 13-month-old lynx1 null striatum. At higher magnification, these nerve fibers displayed intracellular vacuoles and disordered myelin sheaths. Few or none of these morphological alterations were present in younger lynx1 null mutant mice or in heterozygous lynx1 null mutant mice at any age. These data indicate that neuronal health can be maintained by titrating lynx1 dosage and that the lynx1 gene may participate in a trade-off between neuroprotection and augmented learning.

A phase I study of capecitabine, oxaliplatin, and lapatinib in metastatic or advanced solid tumors.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality in the United States, and new treatment options are needed. This phase I study investigated a novel regimen combining 2 chemotherapy drugs with proven efficacy in mCRC (capecitabine and oxaliplatin) with a tyrosine kinase inhibitor (lapatinib). Lapatinib has already been approved by the US Food and Drug Administration for treatment of selected cases of breast cancer. PATIENTS AND METHODS: Patients with solid tumors responsive to fluoropyrimidines or oxaliplatin were eligible for enrollment. Treatment was given over a 21-day cycle with a fixed dosing of intravenous oxaliplatin of 130 mg/m(2) on day 1. Capecitabine and lapatinib were given orally at escalating doses, starting at capecitabine 1500 mg/m(2)/day on days 1-14 and lapatinib 1000 mg daily on days 1-21. RESULTS: Ten patients received treatment per study protocol. All had received previous systemic treatment. Diarrhea was one of the most common side effects and accounted for nearly all grade 3/4 toxicity. The starting dose level was determined to be the maximum tolerated dose. One patient with pancreatic cancer had evidence of a partial response. Three other patients demonstrated stable disease. There were no complete responses. CONCLUSION: Results of this study suggest the regimen of capecitabine, oxaliplatin, and lapatinib has some efficacy in types of advanced or metastatic solid malignancies with known responsiveness to fluoropyrimidines or oxaliplatin. Further research may help determine whether this regimen can improve on the response rates seen with current standard regimens for mCRC.

In vitro heat shock of human monocytes results in a proportional increase of inducible Hsp70 expression according to the basal content.

Heat shock proteins play an important role as molecular chaperones of the cell. Inducible heat shock protein 70 is rapidly synthesised in response to numerous stressors and monocytes are sensitive to changes in core temperature resulting in a circadian variation of Hsp70 expression. Monocytes were isolated via density centrifugation from nine healthy male volunteers at 5 am, 1 pm and 9 pm, representing the nadir (5 am), peak (9 pm) and intermediate (1 pm) of Hsp70 expression in the 24-h cycle. Analysis of freshly isolated monocytes for Hsp70 expression confirmed Hsp70 levels at the three selected time points. Monocytes were subjected to in vitro heat shock at 40 degrees C (+/-0.1) for 90 min with a 90 min 37 degrees C (+/-0.1) exposure acting as a control. A significant increase in Hsp70 was observed at 5 am (p < 0.001) and 1 pm (p = 0.028) at 40 degrees C when compared to 37 degrees C but not at 9 pm (p = 0.19). A significant increase was also observed from the basal levels of Hsp70, measured on freshly isolated monocytes and the levels detected after heat shock at 40 degrees C at 5 am (p < 0.001) and 1 pm (p = 0.001), which was not observed at 9 pm (p = 0.15). Furthermore, a significant correlation was observed in the heat shock response at 40 degrees C and that obtained at 37 degrees C (p < 0.001). In conclusion, the heat shock response in monocytes is directly proportional to the amount of Hsp70 present in the cells and the stress response may be much higher at different times of the day.

Dendritic cells and HNSCC: a potential treatment option? (Review).

Patient survival in head and neck squamous cell cancer (HNSCC) has not changed significantly in many years, despite progress in surgical, radiotherapy and chemotherapy techniques. Immunotherapy, a rapidly progressing alternative cancer treatment, aims to prompt or assist the body's immune system to combat the disease itself. A number of strategies exist including the use of dendritic cells, natural antigen presenting cells capable of stimulating an anti-tumor immune response. Encouraging work has been performed using these cells as vaccines against a number of tumors especially melanoma. Work with head and neck cancer is also encouraging, but less advanced. Dendritic cell presence in head and neck squamous cell cancers is associated with an improved prognosis, however due to immunosuppression, the exact mechanism of which remains poorly understood, these cells do not function efficiently. This prevents the stimulation of an effective anti-tumor immune response by the patient and allows tumor growth to continue. This review summarises the current level of understanding of dendritic cells and their relationship with HNSCC. It briefly summarises work with dendritic cells and other cancers where relevant to HNSCC; dendritic cells and head and neck cancer; the possible causes of dendritic cell impairment; the techniques used to restore their function and the methods used to prime the dendritic cells prior to their use as vaccines for the stimulation of an anti-tumor response.

Effect of hyperopic photorefractive keratectomy on corneal sensitivity: a longitudinal study.

PURPOSE: To investigate corneal sensitivity after photorefractive keratectomy (PRK) for low hyperopia, as measured with a non-invasive stimulus. METHODS: Two experimental groups were recruited: a control group of 17 patients (mean age 61.65 years) who underwent no treatment, and a PRK group of 11 patients (mean age 58.64 years) who underwent one of three attempted hyperopic corrections: +2.00 D (two patients), +3.00 D (four patients), +4.00 D (five patients). Corneal sensitivity was assessed centrally and peripherally, at temporal, medial, and inferior locations, approximately 1 mm from the limbus, using the Non-Contact Corneal Aesthesiometer (NCCA). Measurements were taken at each location for the control group and at preoperative, and postoperative weeks 1 and 2, 1, 3, and 6 months for the PRK group. RESULTS: Comparison of control and PRK groups (preoperative sensation threshold) (t-test): central P=.715, temporal P=.719, medial P=.943, inferior P= .920. Comparison of longitudinal changes in PRK group (one-way ANOVA): central P=.612, temporal P=.997, medial P=.981, inferior P=.993. CONCLUSIONS: Using the Non-Contact Corneal Aesthesiometer, no significant difference was found between the control and PRK groups for preoperative sensation thresholds, and no significant change in corneal sensitivity was found between any of the test time periods at any of the four corneal test locations for the PRK group.