Capecitabine and oral cyclophosphamide: A novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up‐regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28‐day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty‐seven patients entered treatment. The majority of non‐DLT were grades 1 and 2. DLT experienced in the first 8‐week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m²/day capecitabine days 1–28 with 125 mg/m²/day cyclophosphamide days 1–14 of the 28‐day cycle. The recommended phase II dose is therefore 1331 mg/m²/day capecitabine with 100 mg/m²/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.     

Age-specific associations between underlying health conditions and hospitalisation,death and in-hospital death among confirmed COVID-19 cases: a multi-country study based on surveillance data,June to December 2020

BackgroundUnderlying conditions are risk factors for severe COVID-19 outcomes but evidence is limited about how risks differ with age.AimWe sought to estimate age-specific associations between underlying conditions and hospitalisation, death and in-hospital death among COVID-19 cases.MethodsWe analysed case-based COVID-19 data submitted to The European Surveillance System between 2 June and 13 December 2020 by nine European countries. Eleven underlying conditions among cases with only one condition and the number of underlying conditions among multimorbid cases were used as exposures. Adjusted odds ratios (aOR) were estimated using 39 different age-adjusted and age-interaction multivariable logistic regression models, with marginal means from the latter used to estimate probabilities of severe outcome for each condition–age group combination.ResultsCancer, cardiac disorder, diabetes, immunodeficiency, kidney, liver and lung disease, neurological disorders and obesity were associated with elevated risk (aOR: 1.5–5.6) of hospitalisation and death, after controlling for age, sex, reporting period and country. As age increased, age-specific aOR were lower and predicted probabilities higher. However, for some conditions, predicted probabilities were at least as high in younger individuals with the condition as in older cases without it. In multimorbid patients, the aOR for severe disease increased with number of conditions for all outcomes and in all age groups.ConclusionWhile supporting age-based vaccine roll-out, our findings could inform a more nuanced, age- and condition-specific approach to vaccine prioritisation. This is relevant as countries consider vaccination of younger people, boosters and dosing intervals in response to vaccine escape variants.     

Toxicity of titanium dioxide nanoparticles to rainbow trout (Oncorhynchus mykiss): gill injury, oxidative stress, and other physiological effects

Mammalian and in vitro studies have raised concerns about the toxicity of titanium dioxide nanoparticles (TiO2 NPs), but there are very limited data on ecotoxicity to aquatic life. This paper is an observational study where we aim to describe the toxicity of TiO2 NPs to the main body systems of rainbow trout. Stock solutions of dispersed TiO2 NPs were prepared by sonication without using solvents. A semi-static test system was used to expose rainbow trout to either a freshwater control, 0.1, 0.5, or 1.0 mg l(-1) TiO2 NPs for up to 14 days. Exposure to TiO2 NPs caused some gill pathologies including oedema and thickening of the lamellae. No major haematological or blood disturbances were observed in terms of red and white blood cell counts, haematocrit values, whole blood haemoglobin, and plasma Na+ or K+ concentrations. Tissue metal levels (Na+, K+, Ca2+ and Mn) were generally unaffected. However, some exposure concentration-dependent changes in tissue Cu and Zn levels were observed, especially in the brain. Exposure to TiO2 NPs caused statistically significant decreases in Na+K+-ATPase activity (ANOVA, P<0.05) in the gills and intestine, and a trend of decreasing enzyme activity in the brain (the latter was not statistically significant). Thiobarbituric acid reactive substances (TBARS) showed exposure concentration-dependent and statistically significant (ANOVA or Kruskal-Wallis test, P<0.05) increases (two-fold or more) in the gill, intestine and brain, but not the liver during exposure to TiO2 NPs compared to controls. TiO2 NP exposure caused statistically significant (ANOVA, P<0.05) increases in the total glutathione levels in the gills, but depletion of hepatic glutathione compared to controls. Total glutathione levels in the brain and intestine were unaffected. Liver cells exposed to TiO2 NPs showed minor fatty change and lipidosis, and some hepatocytes showed condensed nuclear bodies (apoptotic bodies). Fish probably ingested water containing TiO2 NPs during exposure (stress-induced drinking) which may have resulted in some areas of erosion on the intestinal epithelium. Overall we conclude that titanium dioxide nanoparticles are not a major ionoregulatory toxicant, or haemolytic, at the concentration and exposure times used. Respiratory distress is a concern and sub-lethal toxicity involves oxidative stress, organ pathologies, and the induction of anti-oxidant defences, such as glutathione.     

Haplotype structure,LD blocks,and uneven recombination within the LRP5 gene

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.     

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy,non-mycobacterium bovis BCG-vaccinated Malawian young adults

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M. bovis (MPB70), M. bovis BCG (Ag85), and M. leprae (65 kDa, 35 kDa, and 18 kDa) in >600 non-M. bovis BCG-vaccinated young adults in the Karonga District of northern Malawi. IFN-gamma was measured by enzyme-linked immunosorbent assay (ELISA) in day 6 supernatants of diluted whole-blood cultures. The recombinant M. leprae 35-kDa and 18-kDa and purified native M. bovis BCG Ag85 antigens induced the highest percentages of responders, though both leprosy and bovine tuberculosis are now rare in this population. The M. tuberculosis antigens ESAT-6 and MPT64 and the M. bovis antigen MPB70 induced the lowest percentages of responders. One of the subjects subsequently developed extrapulmonary tuberculosis; this individual had a 15-mm-diameter reaction to the Mantoux test and responded to M. tuberculosis PPD, Ag85, MPT64, and ESAT-6 but not to any of the leprosy antigens. We conclude that in this rural African population, exposure to M. tuberculosis or M. bovis is much less frequent than exposure to environmental mycobacteria such as M. avium, which have antigens homologous to the M. leprae 35-kDa and 18-kDa antigens. M. tuberculosis ESAT-6 showed the strongest association with the size of the Mantoux skin test induration, suggesting that among the three M. tuberculosis antigens tested it provided the best indication of exposure to, or infection with, M. tuberculosis.     

The work of negotiating HIV as a chronic condition: a qualitative analysis

Living with human immunodeficiency virus (HIV) in the industrialised world has for over a decade been conceptualised as living with a chronic illness. People living with HIV now are amongst the first to live and age with the virus. Drawing on a qualitative longitudinal study in a low-incidence area in a low-incidence country, this paper investigates the nuanced ways that people negotiate this condition. While it has been argued that HIV is a condition like any other chronic disease, our thematic analysis reveals some similarities and particularities around living with the condition. In comparing themselves to others with the condition, high levels of diversity of experience were identified that extended well beyond length of time from diagnosis. In comparing their illness with other illnesses, the location, for example, of their specialist service within a clinic for those with acute sexually transmitted diseases was identified as problematic. The work involved in maintaining a coherent sense of self in the face of existing and shifting challenges as a result of their infection was a second strong theme. The final theme involved flux and flex work in the ways people sought to gain and maintain control over various aspects of their lives. All of these experiences are mediated by place; that is the experience is not the same as that of those who live where there is a much higher incidence of infection. The work involved in negotiating this condition in low-incidence environments deserves more attention, but aspects of these findings are significant in higher incidence contexts as well; in particular, passivity in face of infection as one ages and the potential for medication refusal as a means of maintaining control over life and death.     

Healthcare practitioners’ personal and professional values

Personal and professional values of healthcare practitioners influence their clinical decisions. Understanding these values for individuals and across healthcare professions can help improve patient-centred decision-making by individual practitioners and interprofessional teams, respectively. We aimed to identify these values and integrate them into a single framework using Schwartz’s values model. We searched Medline, Embase, PsycINFO, CINAHL and ERIC databases for articles on personal and professional values of healthcare practitioners and students. We extracted values from included papers and synthesized them into a single framework using Schwartz’s values model. We summarised the framework within the context of healthcare practice. We identified 128 values from 50 included articles from doctors, nurses and allied health professionals. A new framework for the identified values established the following broad healthcare practitioner values, corresponding to Schwartz values (in parentheses): authority (power); capability (achievement); pleasure (hedonism); intellectual stimulation (stimulation); critical-thinking (self-direction); equality (universalism); altruism (benevolence); morality (tradition); professionalism (conformity); safety (security) and spirituality (spirituality). The most prominent values identified were altruism, equality and capability. This review identified a comprehensive set of personal and professional values of healthcare practitioners. We integrated these into a single framework derived from Schwartz’s values model. This framework can be used to assess personal and professional values of healthcare practitioners across professional groups, and can help improve practitioners’ awareness of their values so they can negotiate more patient-centred decisions. A common values framework across professional groups can support shared education strategies on values and help improve interprofessional teamwork and decision-making.